Substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines as tyrosine kinase inhibitors

ABSTRACT

A fused bicyclic compound having an effect in inhibition of the activity of a tyrosine kinase, and preparation, compositions, and uses thereof are disclosed. In particular, compounds of formula (I) and (II), or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, a prodrug or an isotopic variation thereof, as well as a pharmaceutical composition including the same are disclosed. Compounds disclosed herein are substituted pyrrolo[3,2-d]pyrimidines and are selective irreversible inhibitors of Bruton&#39;s tyrosine kinase. The described compounds can therefore be used for preventing or treating diseases such as inflammation, autoimmune diseases (such as rheumatoid arthritis), xenogeneic immune diseases and cancers.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a national application of PCT/CN2017/097633filed on Aug. 16, 2017, which claims the priority of the Chinese PatentApplication No. 201610683671.1 filed on Aug. 17, 2016, the entirecontents of each of which are incorporated by reference herein.

FIELD OF THE PRESENT DISCLOSURE

The disclosure belongs to the pharmaceutical field. In particular, thepresent disclosure relates to fused bicyclic compounds which have aninhibitory effect on protein tyrosine kinase activity, pharmaceuticalcompositions containing them, and processes for their preparation anduse.

BACKGROUND OF THE PRESENT DISCLOSURE

Bruton's tyrosine kinase (BTK) belongs to the Tec tyrosine kinasefamily. BTK is mainly expressed in most hematopoietic cells (such as Bcells, mast cells, and macrophages) and is present in bone marrow,spleen, and lymph node tissues. BTK plays an important role in B cellreceptor (BCR) and FcR signaling pathways, which are involved in thedevelopment and differentiation of B cells. BTK can be activated byupstream Src family kinases. Once activated, BTK in turn phosphorylatesPLCγ, which in turn affects B cell function and survival (Humphries etal., J. Biol. Chem. 279: 37651, 2004). These signal paths must beprecisely regulated. Mutations in the gene encoding BTK result in ahuman hereditary B cell-specific immunodeficiency disease, known asX-linked agammaglobulinemia (XLA). Abnormalities in BCR-mediatedsignaling may lead to dysregulation of B cell activation, leading tomany autoimmune and inflammatory diseases. Preclinical studies haveshown that BTK-deficient mice are resistant to the development ofcollagen-induced arthritis. In addition, clinical studies of Rituxan(CD20 antibody) for reducing mature B cells have shown that B cells playa key role in many inflammatory diseases such as rheumatoid arthritis,systemic lupus erythematosus, and multiple sclerosis.

In addition, abnormal activation of BTK plays an important role in thepathogenesis of B-cell lymphoma, which means that inhibition of BTK isuseful in the treatment of hematological malignancies (Davis et al,Nature 463: 88-92, 2010). Preliminary clinical trials have shown thatBruton's tyrosine kinase inhibitor PCI-32765 is effective in thetreatment of several types of B-cell lymphoma. Since BTK acts as amediator in multiple signal transduction pathways, BTK inhibitors havebecome hot spots as anti-inflammatory and/or anti-cancer drugs.

Ibrutinib (PCI-32765) is the first marketed BTK inhibitor in the world.On Nov. 13, 2013, the US Food and Drug Administration (FDA) approved useof Ibrutinib in the treatment of mantle cell lymphoma. In February 2014,the indication for chronic lymphocytic leukemia was added.

However, in order to optimize pharmacokinetics, prolong the drugresistance and reduce toxic side effects, it is necessary to furtherdevelop new BTK inhibitors.

SUMMARY OF THE PRESENT DISCLOSURE

The present disclosure provides a novel fused bicyclic compound and acomposition comprising the same and use thereof. The compounds havebetter BTK kinase inhibitory activity and/or betterpharmacodynamic/pharmacokinetic properties (especially better metabolicstability) and can be used to treat, prevent, and alleviate diseasesmediated by BTK kinase.

Thus, the present disclosure adopts the following technical solutions:

In the first aspect, the present disclosure provides a fused bicycliccompound represented by formula (I):

-   -   wherein,    -   ring A is aromatic ring, ring B is aromatic ring or non-aromatic        ring;    -   X₁ to X₇ are independently selected from C or N atom, wherein,        when X₁, X₂, X₃ and X₆ are C atoms, they are each optionally        substituted by R₁; and when X₆ is C atom, it may be in the        oxidative form of —C(═O)—;    -   wherein, each R₁ is independently selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted        C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,        substituted or unsubstituted C₃-C₇ carbocyclyl, substituted or        unsubstituted C₃-C₇ heterocyclyl, substituted or unsubstituted        C₆-C₁₀ aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl,        —OR_(1a), —N(R_(1a))₂, —SR_(1a), —Si(R_(1a))₃, —C(═O)R_(1a),        —C(═O)OR_(1a), —C(═O)N(R_(1a))₂, —NR_(1a)C(═O)R_(1a),        —NR_(1a)C(═O)OR_(1a), —NR_(1a)C(═O)N(R_(1a))₂, —OC(═O)R_(1a),        —OC(═O)ORia or —OC(═O)N(R_(1a))₂, wherein each R_(1a) is        independently selected from H, substituted or unsubstituted        C₁-C₆ acyl, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl or substituted or        unsubstituted C₅-C₁₀ heteroaryl, or two R_(1a) groups together        form substituted or unsubstituted C₃-C₇ heterocyclyl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   Ar₁ is ring C of the following formula:

-   -   wherein, Y₁ to Y₄ are independently selected from C or N atom,        wherein, when Y₁ to Y₄ are C atoms, they are each optionally        substituted by R₂;    -   wherein each R₂ is independently selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted        C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,        substituted or unsubstituted C₃-C₇ carbocyclyl, substituted or        unsubstituted C₃-C₇ heterocyclyl, substituted or unsubstituted        C₆-C₁₀ aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl,        —OR_(2a), —N(R_(2a))₂, —SR_(2a), —Si(R_(1a))₃, —C(═O)R_(2a),        —C(═O)OR_(2a), —C(═O)N(R_(2a))₂, —NR_(2a)C(═O)R_(2a),        —NR_(2a)C(═O)OR_(2a), —NR_(2a)C(═O)N(R_(2a))₂, —OC(═O)R_(2a),        —OC(═O)OR_(2a) or —OC(═O)N(R_(2a))₂, wherein each R_(2a) is        independently selected from H, substituted or unsubstituted        C₁-C₆ acyl, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl, substituted or        unsubstituted C₅-C₁₀ heteroaryl, or two R_(2a) groups together        form substituted or unsubstituted C₃-C₇ heterocyclyl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   or, Y₁, Y₂ together with their substituent R₂ form substituted        or unsubstituted C₃-C₇ carbocyclyl, substituted or unsubstituted        C₃-C₇ heterocyclyl, substituted or unsubstituted C₆-C₁₀ aryl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   wherein * represents the bond connects with X₇, # represents the        bond connects with L_(a);    -   L_(a) is selected from a bond, O, S, NR₃, C(R₃)₂, C(═O), C(═O)O,        OC(═O), C(═O)NR₃, NR₃C(═O), NR₃C(═O)NR₃, OC(═O)NR₃, NR₃C(═O)O,        S(═O)_(m), S(═O)_(m)NR₃, NR₃S(═O)_(m), NR₃S(═O)_(m)NR₃,        OP(═O)_(m)R₃, P(═O)_(m)OR₃, wherein, each R₃ is independently        selected from H, OH, halo, CN, NO₂, substituted or unsubstituted        C₁-C₆ acyl, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl, substituted or        unsubstituted C₅-C₁₀ heteroaryl, or two R₃ groups together form        substituted or unsubstituted C₃-C₇ heterocyclyl or substituted        or unsubstituted C₅-C₁₀ heteroaryl, m is 1 or 2;    -   Ar₂ is substituted or unsubstituted C₆-C₁₀ aryl or substituted        or unsubstituted C₅-C₁₀ heteroaryl;    -   L is selected from substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or        unsubstituted C₃-C₇ carbocyclyl, substituted or unsubstituted        C₃-C₇ heterocyclyl, substituted or unsubstituted C₆-C₁₀ aryl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   V is selected from a bond, C(═O), C(═O)O, OC(═O), C(═O)NR₄,        NR₄C(═O), NR₄C(═O)NR₄, OC(═O)NR₄, NR₄C(═O)O, S(═O)_(n),        S(═O)_(n)NR₄, NR₄S(═O)_(n), NR₄S(═O)_(n)NR₄, OP(═O)_(n)R₄,        P(═O)_(n)OR₄, wherein, each R₄ is selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ acyl, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₃-C₇ carbocyclyl, substituted or unsubstituted        C₃-C₇ heterocyclyl, substituted or unsubstituted C₆-C₁₀ aryl or        substituted or unsubstituted C₅-C₁₀ heteroaryl, or two R₄ groups        together form substituted or unsubstituted C₃-C₇ heterocyclyl or        substituted or unsubstituted C₅-C₁₀ heteroaryl, n is 1 or 2;    -   R is CN, or C₂-C₆ alkenyl or C₂-C₆ alkynyl that are optionally        substituted by 0, 1, 2 or 3 R₅ substituents, wherein, R₅ is        selected from H, OH, halo, CN, substituted or unsubstituted        C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl or substituted or        unsubstituted C₅-C₁₀ heteroaryl;    -   or a pharmaceutically acceptable salt, a stereoisomer, a        solvate, a hydrate, a polymorph, a prodrug or an isotopic        variants thereof.

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptableexcipient. In a particular embodiment, the compound disclosed herein isprovided in the pharmaceutical composition in an effective amount. In aparticular embodiment, the compound disclosed herein is provided in atherapeutically effective amount. In a particular embodiment, thecompound disclosed herein is provided in a prophylactically effectiveamount.

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptableexcipient, further comprising other therapeutic agents.

In another aspect, the disclosure provides a kit containing a compound,or a pharmaceutically acceptable salt, a stereoisomer, a solvate, ahydrate, a polymorph, a prodrug or an isotopic variants thereof, andother therapeutic agents, and pharmaceutically acceptable carriers,adjuvants or vehicles.

In another aspect, the disclosure provides a method of treating BTKmediated diseases in a subject in need thereof, the method comprising:administering to the subject an effective amount of a compound disclosedherein. In a specific embodiment, the BTK mediated disease is selectedfrom the group consisting of allergic disease, autoimmune disease,inflammatory disease, or cancer.

In a specific embodiment, the BTK mediated disease is B cellproliferative disorder, including, but not limited to, chroniclymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B-celllymphoma, mantle cell lymphoma, follicular lymphoma and chroniclymphocytic leukemia.

In a specific embodiment, the compound is administered orally,subcutaneously, intravenously or intramuscularly. In a specificembodiment, the compound is administered chronically.

Other objects and advantages of the present disclosure will be apparentto those skilled in the art from the specific embodiments, examples andclaims.

Definitions

Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁-C₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂,C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-05, C₃-C₄, C₄-C₆, C₄-C₅ and C₅-C₆alkyl.

It should be understood that when described herein any of the moietiesdefined forth below may be substituted with a variety of substituents,and that the respective definitions are intended to include suchsubstituted moieties within their scope as set out below. Unlessotherwise stated, the term “substituted” is to be defined as set outbelow.

“C₁-C₆ alkyl” (also represented as C₁₋₆ alkyl) refers to astraight-chain or branched saturated hydrocarbon group having from 1 to6 carbon atoms, and it is also referred to herein as “lower alkyl”. Insome embodiments, C₁-C₄ alkyl is particularly preferred. Examples ofalkyl groups include methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl(C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅),3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents; e.g., for instance from 1 to 5 substituents, 1 to3 substituents, or 1 substituent. In certain embodiments, the alkylgroup is unsubstituted C₁-C₆ alkyl (e.g., —CH₃). In certain embodiments,the alkyl group is substituted C₁-C₆ alkyl.

“C₂-C₆ alkenyl” refers to a straight-chain or branched hydrocarbon grouphaving from 2 to 6 carbon atoms, one or more carbon-carbon double bonds(e.g., 1, 2, or 3 carbon-carbon double bonds). The one or morecarbon-carbon double bonds can be internal (such as in 2-butenyl) orterminal (such as in 1-butenyl). In some embodiments, C₂-C₄ alkenyl isparticularly preferred. Examples of alkenyl groups include, but are notlimited to, ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃),1-propen-2-yl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄),pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Unlessotherwise specified, each instance of an alkenyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”)or substituted (a “substituted alkenyl”) with one or more substituentse.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkenyl group is unsubstitutedC₂-C₆ alkenyl. In certain embodiments, the alkenyl group is substitutedC₂-C₆ alkenyl.

“C₂-C₆ alkynyl” refers to a straight-chain or branched hydrocarbon grouphaving from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds(e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one ormore carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon doublebonds). In some embodiments, C₂-C₄ alkynyl is particularly preferred. Incertain embodiments, alkynyl does not contain any double bonds. The oneor more carbon-carbon triple bonds can be internal (such as in2-butynyl) or terminal (such as in 1-butynyl). Examples of the alkynylgroups include, without limitation, ethynyl (C₂), 1-propynyl (C₃),2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅),3-methylbut-1-ynyl (C₅), hexynyl (C₆), and the like. Unless otherwisespecified, each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkynyl group is unsubstitutedC₂-C₆ alkynyl. In certain embodiments, the alkynyl group is substitutedC₂-C₆ alkynyl.

“C₁-C₆ heteroalkyl” refers to an alkyl group, as defined herein, whichfurther contains one or more (e.g., 1, 2, 3 or 4) heteroatoms (e.g.,oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parentcarbon chain, wherein one or more heteroatoms are between adjacentcarbon atoms in the parent carbon chain, and/or one or more heteroatomsare between the carbon atom and the parent molecule, that is, betweenthe connection points. Unless otherwise stated, each heteroalkyl groupis independently substituted, i.e., unsubstituted (“unsubstitutedheteroalkyl”) or substituted with one or more substituents (“substitutedheteroalkyl”). In some embodiments, a heteroalkyl group is anunsubstituted C₁-C₆ heteroalkyl group. In some embodiments, aheteroalkyl group is a substituted C₁-C₆ heteroalkyl group. As aspecific example, the C₁-C₆ heteroalkyl group includes C₁-C₆ alkoxygroup, C₁-C₆ alkylthio group, C₁-C₆ alkylamino group and the like, whichare defined in details as follows.

“C₁-C₆ alkoxy” refers to the group —OR wherein R is a substituted orunsubstituted C₁-C₆ alkyl group. In some embodiments, C₁-C₄ alkoxy groupis particularly preferred. Specific alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

“C₁-C₆ alkylthio” refers to the group —SR wherein R is optionallysubstituted C₁-C₆ alkyl. In some embodiments, C₁-C₄ alkylthio group isparticularly preferred. Specifically, the C₁-C₆ alkylthio groupincludes, but is not limited to, methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, n-pentylthio,n-hexylthio and 1,2-dimethylbutylthio.

“C₁-C₆ alkylamino” refers to the group —NHR or —NR₂, wherein R isoptionally substituted C₁-C₆ alkyl. In some embodiments, C₁-C₄alkylamino group is particularly preferred. Specifically, the C₁-C₆alkylamino group includes, but is not limited to, methylamino,ethylamino, n-propylamino, isopropylamino, n-butylamino, t-butylamino,dimethylamino, methylethylamino and diethylamino.

“C₁-C₆ acyl” refers to the group —(═O)R, wherein R is optionallysubstituted C₁-C₆ alkyl. In some embodiments, C₁-C₄ acyl group isparticularly preferred. Exemplary C₁-C₆ acyl groups include, but are notlimited to, —(═O)CH₃, —(═O)CH₂CH₃, —(═O)CH₂CH₂CH₃ and —(═O)CH(CH₃)₂.

“Halo” or “halogen” means fluorine (F), chlorine (C₁), bromine (Br) andiodine (I). In some embodiments, the halo group is F, —Cl or Br. In someembodiments, the halogen group is F or C₁. In some embodiments, thehalogen group is F.

Thus, “C₁-C₆ haloalkyl” and “C₁-C₆ haloalkoxy” refer to the above “C₁-C₆alkyl” and “C₁-C₆ alkoxy”, which are substituted by one or more halogroups. In some embodiments, C₁-C₄ haloalkyl group is particularlypreferred, and more preferably C₁-C₂ haloalkyl group. In someembodiments, C₁-C₄ haloalkoxy group is particularly preferred, and morepreferably C₁-C₂ haloalkoxy group. Exemplary haloalkyl groups include,but are not limited to, —CF₃, —CH₂F, —CHF₂, —CHFCH₂F, —CH₂CHF₂, —CF₂CF₃,—CCl₃, —CH₂C₁, —CHCl₂, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.Exemplary haloalkoxy groups include, but are not limited to: —OCH₂F,—OCHF₂, —OCF₃, and the like.

“C₃-C₇ carbocyclyl” refers to a non-aromatic cyclic hydrocarbon grouphaving from 3 to 7 ring carbon atoms and zero heteroatoms. In someembodiments, C₅-C₆ carbocyclyl is preferred, which is a non-aromaticcyclic hydrocarbon group having from 5 to 6 ring carbon atoms and zeroheteroatoms. In some embodiments, C₄ carbocyclyl is preferred, which isa non-aromatic cyclic hydrocarbon group having 4 ring carbon atoms andzero heteroatoms. In some embodiments, C₅ carbocyclyl is preferred,which is a non-aromatic cyclic hydrocarbon group having 5 ring carbonatoms and zero heteroatoms. In some embodiments, C₆ carbocyclyl ispreferred, which is a non-aromatic cyclic hydrocarbon group having 6ring carbon atoms and zero heteroatoms. Carbocyclyl also includes ringsystems wherein the carbocyclyl ring, as defined above, is fused,bridged or spiro-connected with one or more carbocyclyl, heterocyclyl,aryl or heteroaryl groups wherein the point of attachment is on thecarbocyclyl ring, and in such instances, the number of carbons continueto designate the number of carbons in the carbocyclic ring system.Exemplary carbocyclyl groups include, but is not limited to, cyclopropyl(C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexyl(C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), as well as cycloheptyl(C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Unless otherwise specified,each instance of a carbocyclyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) orsubstituted (a “substituted carbocyclyl”) with one or more substituents.In certain embodiments, the carbocyclyl group is unsubstituted C₃-C₇carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃-C₇ carbocyclyl.

“C₃-C₇ heterocyclyl” refers to a radical of a 3- to 7-memberednon-aromatic ring system having ring carbon atoms and 1 to 3 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon, wherein thecarbon, nitrogen, sulfur and phosphorus atoms may be present in theoxidation state, such as C(O), S(O), S(O)₂, P(O), and the like. Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Insome embodiments, C₄-C₇ heterocyclyl is preferred, which is a radical ofa 4- to 7-membered non-aromatic ring system having ring carbon atoms and1 to 3 ring heteroatoms. In some embodiments, C₄-C₆ heterocyclyl ispreferred, which is a radical of a 4- to 6-membered non-aromatic ringsystem having ring carbon atoms and 1 to 3 ring heteroatoms. In someembodiments, C₅-C₆ heterocyclyl is preferred, which is a radical of a 5-to 6-membered non-aromatic ring system having ring carbon atoms and 1 to3 ring heteroatoms. In some embodiments, C₅ heterocyclyl is preferred,which is a radical of a 5-membered non-aromatic ring system having ringcarbon atoms and 1 to 3 ring heteroatoms. In some embodiments, the abovementioned heterocyclyl contain 1 to 3 (more preferably 1 or 2) ringheteroatoms selected from nitrogen, oxygen and sulfur (preferablynitrogen and oxygen). Unless otherwise specified, each instance ofheterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted C₃-C₇ heterocyclyl.In certain embodiments, the heterocyclyl group is substituted C₃-C₇heterocyclyl. Heterocyclyl also includes ring systems wherein theheterocyclyl ring, as defined above, is fused, bridged orspiro-connected with one or more carbocyclyl, heterocyclyl, aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring; and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system. Exemplary 3-membered heterocyclyl groups containing oneheteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxathiolanyl, oxathiolyl (1,2-oxathiolyl, 1,3-oxathiolyl), dithiolanyl,dihydropyrazolyl, dihydroimidazolyl, dihydrothiazolyl,dihydroisothiazolyl, dihydrooxazolyl, dihydroisoxazolyl,dihydrooxadiazolyl and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, and thianyl. Exemplary 6-membered heterocyclylgroups containing two heteroatoms include, without limitation,dihydropyrazinyl, piperazinyl, morpholinyl, dithianyl, dioxanyl.Exemplary 6-membered heterocyclyl groups containing three heteroatomsinclude, without limitation, triazinanyl. Exemplary 7-memberedheterocyclyl groups containing one or two heteroatoms include, withoutlimitation, azepanyl, diazepanyl, oxepanyl and thiepanyl. Exemplary5-membered heterocyclyl groups fused to a 6-membered aryl ring (alsoreferred to herein as a 5,6-bicyclic heterocyclic ring) include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary6-membered heterocyclyl groups fused to an 6-membered aryl ring (alsoreferred to herein as a 6,6-bicyclic heterocyclic ring) include, withoutlimitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“C₆-C₁₀ aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 πelectrons shared in a cyclic array) having 6-10 ring carbon atoms andzero heteroatoms provided in the aromatic ring system. In someembodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has ten ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). “C₆-C₁₀aryl” also includes ring systems wherein the aryl ring, as definedabove, is fused with one or more carbocyclyl, heterocyclyl, aryl orheteroaryl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₀ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₀ aryl.

“C₅-C₁₀ heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur.In some embodiments, C₅ heteroaryl is preferred, which is a radical of a5-membered monocyclic 4n+2 aromatic ring system (e.g., having 6 πelectrons shared in a cyclic array) having ring carbon atoms and 1-4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen and sulfur. In some embodiments, C₆ heteroaryl ispreferred, which is a radical of a 6-membered monocyclic 4n+2 aromaticring system (e.g., having 6 π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur. In heteroarylgroups that contain one or more nitrogen atoms, the point of attachmentcan be a carbon or nitrogen atom, as valency permits. Heteroarylbicyclic ring systems can include one or more heteroatoms in one or bothrings. Heteroaryl includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl, heterocyclyl, arylor heteroaryl groups wherein the point of attachment is on theheteroaryl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heteroaryl ringsystem. Unless otherwise specified, each instance of a heteroaryl groupis independently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted C₅-C₁₀ heteroaryl. In certain embodiments, theheteroaryl group is substituted C₅-C₁₀ heteroaryl. Exemplary 5-memberedheteroaryl groups containing one heteroatom include, without limitation,pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groupscontaining two heteroatoms include, without limitation, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary5-membered heteroaryl groups containing three heteroatoms include,without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary5-membered heteroaryl groups containing four heteroatoms include,without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted groups. Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, any of the substituentsdescribed herein that results in the formation of a stable compound. Forpurposes of this disclosure, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary substituents on carbon atom include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), alkyl,haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

-   -   or two geminal hydrogens on a carbon atom are replaced with the        group ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa),        ═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or        ═NOR^(cc);    -   each instance of R^(aa) is, independently, selected from alkyl,        haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,        and heteroaryl, or two R^(aa) groups are joined to form a        heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl,        alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is        independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)        groups;    -   each instance of R^(bb) is, independently, selected from        hydrogen, —OH, —OR^(aa), —N(R″)₂, —CN, —C(═O)R^(aa),        —C(═O)N(R″)₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),        —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),        —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),        —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,        —P(═O)(NR^(cc))₂, alkyl, haloalkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R^(bb)        groups are joined to form a heterocyclyl or heteroaryl ring,        wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,        aryl, and heteroaryl is independently substituted with 0, 1, 2,        3, 4, or 5 R^(dd) groups;    -   each instance of R^(cc) is, independently, selected from        hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl,        heterocyclyl, aryl, and heteroaryl, or two R^(cc) groups are        joined to form a heterocyclyl or heteroaryl ring, wherein each        alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and        heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5        R^(dd) groups;    -   each instance of R^(dd) is, independently, selected from        halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee),        —ON(R^(ff))₂, —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff),        —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee),        —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂,        —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂,        —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee),        —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,        —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee),        —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),        —S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,        —C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),        —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, alkyl,        haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,        heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,        heterocyclyl, aryl, and heteroaryl is independently substituted        with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd)        substituents can be joined to form ═O or ═S;    -   each instance of R^(ee) is, independently, selected from alkyl,        haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl,        and heteroaryl, wherein each alkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently        substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;    -   each instance of e is, independently, selected from hydrogen,        alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,        aryl and heteroaryl, or two e groups are joined to form a        heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl,        alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is        independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)        groups; and each instance of R^(gg) is, independently, halogen,        —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆        alkyl)₂, —N(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂        ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),        —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),        —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆        alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl),        —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆        alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆        alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆        alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆        alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆        alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆        alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂,        —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,        —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆        alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,        —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl,        —P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂,        —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl, C₆-C₁₀ aryl, C₃-C₇        heterocyclyl, C₅-C₁₀ heteroaryl; or two geminal R^(gg)        substituents can be joined to form ═O or ═S; wherein X⁻ is a        counterion.

Exemplary substituents on nitrogen atoms include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R″)₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R″,—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,alkyl, perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl, or two R^(cc) groups attached to a nitrogen atom arejoined to form a heterocyclyl or heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of the present disclosure include those derivedfrom suitable inorganic and organic acids and inorganic and organicbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orsalts of organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid. Also includedherein is the salt formed by using the conventional methods in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Pharmaceutically acceptable salts derived from appropriate basesinclude alkali metal, alkaline earth metal, ammonium and N⁺ (C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium salts, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or elderly adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound disclosed herein may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutically effective amount and prophylactically effective amount.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

“Combination” and related terms mean the simultaneous or sequentialadministration of a compound and other therapeutic agent of the presentdisclosure. For example, a compound disclosed herein may be administeredsimultaneously or sequentially with another therapeutic agent inseparate unit dosage forms, or together with another therapeutic agentin a single unit dosage form.

The compounds disclosed herein can be used to treat or prevent diseasesmediated by Bruton's Tyrosine Kinase (BTK). BTK mediated diseases asused herein, mean any disease state or other deleterious condition inwhich B cells, mast cells, myeloid cells or osteoclasts play a centralrole. These diseases include but are not limited to, immune, autoimmuneand inflammatory diseases, allergies, infectious diseases, boneresorption disorders and proliferative diseases.

Immune, autoimmune and inflammatory diseases that can be treated orprevented with the compounds disclosed herein include rheumatic diseases(e.g. rheumatoid arthritis, psoriatic arthritis, infectious arthritis,progressive chronic arthritis, deforming arthritis, osteoarthritis,traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis,acute synovitis and spondylitis), glomerulonephritis (with or withoutnephrotic syndrome), autoimmune hematologic disorders (e.g. hemolyticanemia, aplasic anemia, idiopathic thrombocytopenia, and neutropenia),autoimmune gastritis, and autoimmune inflammatory bowel diseases (e.g.ulcerative colitis and Crohn's disease), host versus graft disease,allograft rejection, chronic thyroiditis, Graves' disease, schleroderma,diabetes (type I and type II), active hepatitis (acute and chronic),pancreatitis, primary billiary cirrhosis, myasthenia gravis, multiplesclerosis, systemic lupus erythematosis, psoriasis, atopic dermatitis,contact dermatitis, eczema, skin sunburns, vasculitis (e.g. Behcet'sdisease), chronic renal insufficiency, Stevens-Johnson syndrome,inflammatory pain, idiopathic sprue, cachexia, sarcoidosis,Guillain-Barre syndrome, uveitis, conjunctivitis, kerato conjunctivitis,otitis media, periodontal disease, pulmonary interstitial fibrosis,asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonaryinsufficiency syndrome, pulmonary emphysema, pulmonary fibrosis,silicosis, chronic inflammatory pulmonary disease (e.g. chronicobstructive pulmonary disease) and other inflammatory or obstructivedisease on airways.

Allergies that can be treated or prevented include, among others,allergies to foods, food additives, insect poisons, dust mites, pollen,animal materials and contact allergens, type I hypersensitivity allergicasthma, allergic rhinitis, allergic conjunctivitis.

Infectious diseases that can be treated or prevented include, amongothers, sepsis, septic shock, endotoxic shock, sepsis by Gram-negativebacteria, shigellosis, meningitis, cerebral malaria, pneumonia,tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitisB and hepatitis C), HIV infection, retinitis caused by cytomegalovirus,influenza, herpes, treatment of infections associated with severe burns,myalgias caused by infections, cachexia secondary to infections, andveterinary viral infections such as lentivirus, caprine arthritic virus,visna-maedi virus, feline immunodeficiency virus, bovineimmunodeficiency virus or canine immunodeficiency virus.

Bone resorption disorders that can be treated or prevented include,among others, osteoporosis, osteoarthritis, traumatic arthritis, goutyarthritis and bone disorders related with multiple myeloma.

Proliferative diseases that can be treated or prevented include, amongothers, non-Hodgkin lymphoma (in particular the subtypes diffuse largeB-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)), B cell chroniclymphocytic leukemia and acute lymphoblastic leukemia (ALL) with matureB cell.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Compound

In the present disclosure, “compound disclosed herein” refers to thefollowing compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, a solvate, a hydrate, a polymorph, a prodrug or anisotopic variants thereof.

In one embodiment, the present disclosure relates to a compound offormula (I):

-   -   wherein,    -   ring A is aromatic ring, ring B is aromatic ring or non-aromatic        ring;    -   X₁ to X₇ are independently selected from C or N atom, wherein,        when X₁, X₂, X₃ and X₆ are C atoms, they are each optionally        substituted by R₁; and when X₆ is C atom, it may be in the        oxidative form of —C(═O)—;    -   wherein, each R₁ is independently selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted        C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,        substituted or unsubstituted C₃-C₇ carbocyclyl, substituted or        unsubstituted C₃-C₇ heterocyclyl, substituted or unsubstituted        C₆-C₁₀ aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl,        —OR_(1a), —N(R_(1a))₂, —SR_(1a), —Si(R_(1a))₃, —C(═O)R_(1a),        —C(═O)OR_(1a), —C(═O)N(R_(1a))₂, —NR_(1a)C(═O)R_(1a),        —NR_(1a)C(═O)OR_(1a), —NR_(1a)C(═O)N(R_(1a))₂, —OC(═O)R_(1a),        —OC(═O)OR_(1a) or —OC(═O)N(R_(1a))₂, wherein each R_(1a) is        independently selected from H, substituted or unsubstituted        C₁-C₆ acyl, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl or substituted or        unsubstituted C₅-C₁₀ heteroaryl, or two R_(1a) groups together        form substituted or unsubstituted C₃-C₇ heterocyclyl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   Ar₁ is ring C of the following formula:

-   -   wherein, Y₁ to Y₄ are independently selected from C or N atom,        wherein, when Y₁ to Y₄ are C atoms, they are each optionally        substituted by R₂;    -   wherein each R₂ is independently selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted        C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,        substituted or unsubstituted C₃-C₇ carbocyclyl, substituted or        unsubstituted C₃-C₇ heterocyclyl, substituted or unsubstituted        C₆-C₁₀ aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl,        —OR_(2a), —N(R_(2a))₂, —SR_(2a), —Si(R_(1a))₃, —C(═O)R_(2a),        —C(═O)OR_(2a), —C(═O)N(R_(2a))₂, —NR_(2a)C(═O)R_(2a),        —NR_(2a)C(═O)OR_(2a), —NR_(2a)C(═O)N(R_(2a))₂, —OC(═O)R_(2a),        —OC(═O)OR_(2a) or —OC(═O)N(R_(2a))₂, wherein each R_(2a) is        independently selected from H, substituted or unsubstituted        C₁-C₆ acyl, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl, substituted or        unsubstituted C₅-C₁₀ heteroaryl, or two R_(2a) groups together        form substituted or unsubstituted C₃-C₇ heterocyclyl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   or, Y₁, Y₂ together with their substituent R₂ form substituted        or unsubstituted C₃-C₇ carbocyclyl, substituted or unsubstituted        C₃-C₇ heterocyclyl, substituted or unsubstituted C₆-C₁₀ aryl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   wherein * represents the bond connects with X₇, # represents the        bond connects with L_(a);    -   L_(a) is selected from a bond, O, S, NR₃, C(R₃)₂, C(═O), C(═O)O,        OC(═O), C(═O)NR₃, NR₃C(═O), NR₃C(═O)NR₃, OC(═O)NR₃, NR₃C(═O)O,        S(═O)_(m), S(═O)_(m)NR₃, NR₃S(═O)_(m), NR₃S(═O)_(m)NR₃,        OP(═O)_(m)R₃, P(═O)_(m)OR₃, wherein, each R₃ is independently        selected from H, OH, halo, CN, NO₂, substituted or unsubstituted        C₁-C₆ acyl, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl, substituted or        unsubstituted C₅-C₁₀ heteroaryl, or two R₃ groups together form        substituted or unsubstituted C₃-C₇ heterocyclyl or substituted        or unsubstituted C₅-C₁₀ heteroaryl, m is 1 or 2;    -   Ar₂ is substituted or unsubstituted C₆-C₁₀ aryl or substituted        or unsubstituted C₅-C₁₀ heteroaryl;    -   L is selected from substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or        unsubstituted C₃-C₇ carbocyclyl, substituted or unsubstituted        C₃-C₇ heterocyclyl, substituted or unsubstituted C₆-C₁₀ aryl or        substituted or unsubstituted C₅-C₁₀ heteroaryl;    -   V is selected from a bond, C(═O), C(═O)O, OC(═O), C(═O)NR₄,        NR₄C(═O), NR₄C(═O)NR₄, OC(═O)NR₄, NR₄C(═O)O, S(═O)_(n),        S(═O)_(n)NR₄, NR₄S(═O)_(n), NR₄S(═O)_(n)NR₄, OP(═O)_(n)R₄,        P(═O)_(n)OR₄, wherein, each R₄ is independently selected from H,        OH, halo, CN, NO₂, substituted or unsubstituted C₁-C₆ acyl,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆        alkynyl, substituted or unsubstituted C₃-C₇ carbocyclyl,        substituted or unsubstituted C₃-C₇ heterocyclyl, substituted or        unsubstituted C₆-C₁₀ aryl or substituted or unsubstituted C₅-C₁₀        heteroaryl, or two R₄ groups together form substituted or        unsubstituted C₃-C₇ heterocyclyl or substituted or unsubstituted        C₅-C₁₀ heteroaryl, n is 1 or 2;    -   R is CN or C₂-C₆ alkenyl or C₂-C₆ alkynyl that are optionally        substituted by 0, 1, 2 or 3 R₅ substituents, wherein, R₅ is        selected from H, OH, halo, CN, substituted or unsubstituted        C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₇        carbocyclyl, substituted or unsubstituted C₃-C₇ heterocyclyl,        substituted or unsubstituted C₆-C₁₀ aryl or substituted or        unsubstituted C₅-C₁₀ heteroaryl;    -   or a pharmaceutically acceptable salt, a stereoisomer, a        solvate, a hydrate, a polymorph, a prodrug or an isotopic        variants thereof.

Preferably, in the above mentioned embodiment, the compound is acompound of formula (II):

-   -   wherein, X₃, X₆, R₁, Ar₁, L_(a), Ar₂, L, V and R are as defined        above.

Preferably, in the above mentioned embodiment, the compound is thefollowing compound:

-   -   wherein, Ar₁, L_(a), Ar₂, L, V and R are as defined above.

Preferably, in the above mentioned embodiment, at least one of Y₁ to Y₄is N atom, and the others are C atoms; or, preferably, in the abovementioned embodiment, Y₁ to Y₄ are all C atoms; and when they are Catoms, each of them is optionally substituted by R₂;

-   -   preferably, Ar₁ is selected from the following groups:

-   -   wherein, R₂ is independently selected from H, OH, halo, CN, NO₂,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted        C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,        substituted or unsubstituted C₃-C₇ carbocyclyl, substituted or        unsubstituted C₃-C₇ heterocyclyl, substituted or unsubstituted        C₆-C₁₀ aryl or substituted or unsubstituted C₅-C₁₀ heteroaryl;        preferably, R₂ is independently selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ alkyl or substituted or        unsubstituted C₁-C₆ heteroalkyl; preferably, R₂ is independently        selected from H, OH, halo or CN; preferably, R₂ is independently        selected from H or halo, preferably, R₂ is H.

Preferably, in the above mentioned embodiment, L_(a) is selected from abond, O, S, NR₃, C(R₃)₂, C(═O), C(═O)O, OC(═O), C(═O)NR₃, NR₃C(═O),NR₃C(═O)NR₃, OC(═O)NR₃, NR₃C(═O)O, S(═O)_(m), S(═O)_(m)NR₃, NR₃S(═O)_(m)or NR₃S(═O)_(m)NR₃; preferably, L_(a) is selected from a bond, O, S,NR₃, C(R₃)₂, C(═O), C(═O)O, OC(═O), C(═O)NR₃, NR₃C(═O), NR₃C(═O)NR₃,OC(═O)NR₃ or NR₃C(═O)O; preferably, L_(a) is selected from a bond, O, S,NR₃, C(R₃)₂, C(═O), C(═O)O, OC(═O), C(═O)NR₃ or NR₃C(═O); preferably,L_(a) is selected from O, S, NR₃, C(R₃)₂ or C(═O)NR₃; preferably, L_(a)is selected from O or C(═O)NR₃; preferably, L_(a) is O;

-   -   wherein, each R₃ is independently selected from H, OH, halo, CN,        NO₂, substituted or unsubstituted C₁-C₆ acyl or substituted or        unsubstituted C₁-C₆ alkyl; preferably, R₃ is independently        selected from H, OH, halo, CN or NO₂; preferably, R₃ is        independently selected from H, OH, F, C₁ or Br; preferably, R₃        is H or F;    -   m is 1 or 2.

Preferably, in the above mentioned embodiment, Ar₂ is unsubstitutedC₆-C₁₀ aryl or unsubstituted C₅-C₁₀ heteroaryl; preferably, Ar₂ isphenyl or pyridinyl.

Preferably, in the above mentioned embodiment, L is selected fromsubstituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₇ carbocyclyl,substituted or unsubstituted C₃-C₇ heterocyclyl, substituted orunsubstituted C₆-C₁₀ aryl or substituted or unsubstituted C₅-C₁₀heteroaryl;

-   -   preferably, L is selected from C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted        C₃-C₇ carbocyclyl or substituted or unsubstituted C₃-C₇        heterocyclyl;    -   preferably, L is selected from substituted or unsubstituted        C₅-C₆ heterocyclyl;    -   preferably, L is selected from the following groups:

-   -   preferably, L is selected from the following groups:

-   -   wherein        represents the connection position between X₅ of the parent core        and V.

Preferably, in the above mentioned embodiment, V is selected from abond, C(═O), C(═O)O, OC(═O), C(═O)NR₄, NR₄C(═O), NR₄C(═O)NR₄, OC(═O)NR₄,NR₄C(═O)O, S(═O)_(n), S(═O)_(n)NR₄, NR₄S(═O)_(n), NR₄S(═O)_(n)NR₄,OP(═O)_(n)R₄ or P(═O)_(n)OR₄; preferably, V is selected from a bond,C(═O), C(═O)O, OC(═O), C(═O)NR₄, NR₄C(═O), NR₄C(═O)NR₄, OC(═O)NR₄,NR₄C(═O)O, S(═O)_(n), S(═O)_(n)NR₄, NR₄S(═O)_(n) or NR₄S(═O)_(n)NR₄;preferably, V is selected from a bond, C(═O), C(═O)O, OC(═O), C(═O)NR₄,NR₄C(═O), NR₄C(═O)NR₄, OC(═O)NR₄ or NR₄C(═O)O; preferably, V is selectedfrom a bond, C(═O), C(═O)O, OC(═O), C(═O)NR₄ or NR₄C(═O); preferably, Vis selected from a bond or C(═O); preferably, V is C(═O);

-   -   wherein, each R₄ is selected from H, OH, halo, CN, NO₂,        substituted or unsubstituted C₁-C₆ acyl or substituted or        unsubstituted C₁-C₆ alkyl; preferably, R₄ is independently        selected from H or substituted or unsubstituted C₁-C₆ alkyl;    -   n is 1 or 2.

Preferably, in the above mentioned embodiment, R is CN, or C₂-C₆ alkenylor C₂-C₆ alkynyl that are optionally substituted by 0 or 1 R₅substituents; preferably, R is C₂-C₆ alkenyl or C₂-C₆ alkynyl that areoptionally substituted by 0 or 1 R₅ substituents; preferably, R is C₂-C₆alkenyl that is optionally substituted by 0 or 1 R₅ substituents;preferably, R is unsubstituted vinyl;

-   -   R₅ is selected from H, OH, halo, CN, substituted or        unsubstituted C₁-C₆ alkyl or substituted or unsubstituted C₁-C₆        heteroalkyl; preferably, R₅ is selected from H, CN, substituted        or unsubstituted C₁-C₆ alkyl or substituted or unsubstituted        C₁-C₆ heteroalkyl;    -   preferably, in the above mentioned embodiment, R is selected        from the following groups:

-   -   wherein, each Ra, R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) is        selected from the above R₅;    -   preferably, R is selected from the following groups:

Preferably, in the above mentioned embodiment, the compound is acompound of formula (III):

-   -   wherein,    -   -L-V—R is selected from:

-   -   preferably, -L-V—R is selected from:

-   -   Ar₁-L_(a)-AR₂ is selected from:

-   -   X₆ is CH or N.

Preferably, in the above mentioned embodiment, the compound of formula(I) may be selected from the following compound:

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer (such as cis- and trans-isomer), or can be in the form of amixture of stereoisomers, including racemic mixtures and mixturesenriched in one or more stereoisomer. Isomers can be isolated frommixtures by methods known to those skilled in the art, including chiralhigh pressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts; or preferred isomers can be prepared byasymmetric syntheses.

Also disclosed herein are all suitable isotopical variants of thecompounds disclosed herein. An isotope derivative of a compounddisclosed herein is defined as wherein at least one atom is replaced byan atom having the same atomic number but differing in atomic mass fromthe atomic mass typically found in nature. Examples of isotopes that canbe incorporated into compounds disclosed herein include hydrogen,carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, and chlorineisotopes, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³¹P, ³²P, ³⁵Sand ³⁶Cl, respectively. Certain isotopical variants of the compoundsdisclosed herein, such as the radioisotopes of ³H and ¹⁴C areincorporated are useful in the tissue distribution experiments of drugsand substrates. Tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C areparticularly preferred for their ease of preparation and detectability.In addition, substitution with heavier isotopes such as deuterium, i.e.,²H, has therapeutic advantages due to its good metabolic stability, forexample, increased half-life in vivo or reduced dosage, and is thuspreferable in some cases. Isotopical variants of the compounds disclosedherein can be prepared conventionally by the following procedures, forexample by descriptive methods or by the preparations described in theExamples below, using appropriate reagents containing appropriateisotopes.

After study and research, the present inventors have unexpectedlydiscovered that the deuterated compound of the fused bicyclic compounddisclosed herein and its pharmaceutically acceptable salt haveequivalent or superior pharmacokinetics and/or pharmacodynamicsproperties, as compared with the non-deuterated compound of the fusedbicyclic compound disclosed herein. It is thus suitable for use as acompound to inhibit BTK kinase and is more suitable for the preparationof a medicament for treating cancer and BTK kinase-related diseases.

The compound of the present disclosure or a pharmaceutically acceptablesalt thereof may be in an amorphous or crystalline form. Furthermore,the compounds of the present disclosure may exist in one or morecrystalline forms. Accordingly, the disclosure includes within its scopeall amorphous or crystalline forms of the compounds disclosed herein.

Those skilled in the art will appreciate that many organic compounds canform complexes with solvents that react in or precipitate or crystallizefrom the solvent. These complexes are referred to as “solvates.” Whenthe solvent is water, the complex is referred to as a “hydrate.” Thedisclosure encompasses all solvates of the compounds disclosed herein.

In addition, prodrugs are also included within the context of thepresent disclosure. The term “prodrug” as used herein refers to acompound which is converted in vivo to an active form thereof having amedical effect by, for example, hydrolysis in blood. Pharmaceuticallyacceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugsas Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S.Ramon and H. Barbra “Improved oral drug delivery: solubility limitationsovercome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996)19(2) 115-130, each is incorporated herein by reference.

A prodrug is any covalently bonded carrier which, when administered to apatient, releases the compound disclosed herein in vivo. Prodrugs aretypically prepared by modifying functional groups in such a way that themodifications of the prodrug can be cleaved in vivo to yield the parentcompound. Prodrugs include, for example, compounds disclosed hereinwherein a hydroxy, amino or sulfhydryl group is bonded to any groupwhich, when administered to a patient, can be cleaved to form a hydroxy,amino or sulfhydryl group. Thus, representative examples of prodrugsinclude, but are not limited to, covalent derivative formed by hydroxyl,amino or mercapto functional groups of the compounds disclosed hereinreacted with acetic acid, formic acid or benzoic acid. Further, in thecase of a carboxylic acid (—COOH), an ester such as a methyl ester, anethyl ester or the like can be used. The ester itself may be activeand/or may hydrolyze under conditions in human bodies. Suitablepharmaceutically acceptable hydrolysable in vivo ester groups includethose groups which readily decompose in the human body to release theparent acid or a salt thereof.

Pharmaceutical Compositions, Formulations and Kits

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound of the present disclosure (also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

A pharmaceutically acceptable excipient for use in the presentdisclosure refers to a non-toxic carrier, adjuvant or vehicle which doesnot destroy the pharmacological activity of the compound formulatedtogether. Pharmaceutically acceptable carriers, adjuvants, or vehiclesthat can be used in the compositions of the present disclosure include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins (e.g., human serum albumin), buffer substances(such as phosphate), glycine, sorbic acid, potassium sorbate, a mixtureof partial glycerides of saturated plant fatty acids, water, salt orelectrolyte (such as protamine sulfate), disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel,magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax,polyethylene-polyoxypropylene block polymers, polyethylene glycol andlanolin.

The present disclosure also includes kits (e.g., pharmaceutical packs).Kits provided may include a compound disclosed herein, other therapeuticagents, and a first and a second containers (eg, vials, ampoules,bottles, syringes, and/or dispersible packages or other materials)containing the compound disclosed herein or other therapeutic agents. Insome embodiments, kits provided can also optionally include a thirdcontainer containing a pharmaceutically acceptable excipient fordiluting or suspending the compound disclosed herein and/or othertherapeutic agent. In some embodiments, the compound disclosed hereinprovided in the first container and the other therapeutic agentsprovided in the second container is combined to form a unit dosage form.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisdisclosure. The present disclosure, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 0.3-30 mg tablets(0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 30-90 mg tablets (10-30mg of active compound per tablet) in a tablet press.

Exemplary Formulation 3—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 90-150 mg tablets(30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 4—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 150-240 mg tablets(50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 5—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 240-270 mg tablets(80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 6—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 270-450 mg tablets(90-150 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 450-900 mg tablets(150-300 mg of active compound) in a tablet press.

Exemplary Formulation 8—Capsules: A compound of the present disclosuremay be admixed as a dry powder with a starch diluent in an approximate1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg ofactive compound per capsule).

Exemplary Formulation 9—Liquid: A compound of the present disclosure(125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) andthe resultant mixture may be blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously made solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water may then be addedto produce a total volume of 5 mL.

Exemplary Formulation 10—Injection: A compound of the present disclosuremay be dissolved or suspended in a buffered sterile saline injectableaqueous medium to a concentration of approximately 5 mg/mL.

Administration

The pharmaceutical composition provided by the present disclosure can beadministered by a variety of routes including, but not limited to, oraladministration, parenteral administration, inhalation administration,topical administration, rectal administration, nasal administration,oral administration, vaginal administration, administration by implantor other means of administration. For example, parenteral administrationas used herein includes subcutaneous administration, intradermaladministration, intravenous administration, intramuscularadministration, intra-articular administration, intraarterialadministration, intrasynovial administration, intrasternaladministration, intracerebroventricular administration, intralesionaladministration, and intracranial injection or infusion techniques.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the disorder disclosed herein, the compoundsprovided herein will be administered to a subject at risk for developingthe condition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compostions of the present disclosure may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to rapidly raise the concentration of the compound in theblood to an effective level. The bolus dose depends on the systemiclevels of the active ingredient desired, e.g., an intramuscular orsubcutaneous bolus dose allows a slow release of the active ingredient,while a bolus delivered directly to the veins (e.g., through an IV drip)allows a much faster delivery which quickly raises the concentration ofthe active ingredient in the blood to an effective level. In otherembodiments, the pharmaceutical composition may be administered as acontinuous infusion, e.g., by IV drip, to provide maintenance of asteady-state concentration of the active ingredient in the subject'sbody. Furthermore, in still yet other embodiments, the pharmaceuticalcomposition may be administered as first as a bolus dose, followed bycontinuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional dermal penetration ingredientsto enhance the stability of the active ingredients or Formulation.

All such known transdermal formulations and ingredients are includedwithin the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present disclosure can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present disclosure also relates to the pharmaceutically acceptableformulations of a compound of the present disclosure. In one embodiment,the formulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin (e.g., 10-50% in water).

Treatment

The compounds disclosed herein and pharmaceutical compositions thereofcan be used to treat or prevent a variety of conditions or diseasesmediated by Bruton's Tyrosine kinase (BTK). Such conditions and diseasesinclude, but are not limited to: (1) arthritis, including rheumatoidarthritis, juvenile arthritis, psoriatic arthritis and osteoarthritis;(2) asthma and other obstructive airways diseases, including chronicasthma, late asthma, airway hyper-responsiveness, bronchitis, bronchialasthma, allergic asthma, intrinsic asthma, extrinsic asthma, dustasthma, adult respiratory distress syndrome, recurrent airwayobstruction, and chronic obstruction pulmonary disease includingemphysema; (3) autoimmune diseases or disorders, including thosedesignated as single organ or single cell-type autoimmune disorders, forexample Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmuneatrophic gastritis of pernicious anemia, autoimmune encephalomyelitis,autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopeniaincluding idiopathic thrombopenic purpura, sympathetic ophthalmia,myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronicaggressive hepatitis, ulcerative colitis and membranous glomerulopathy,those designated as involving systemic autoimmune disorder, for examplesystemic lupus erythematosis, immune thrombocytopenic purpura,rheumatoid arthritis, Sjogren's syndrome, Eiter's syndrome,polymyositis- dermatomyositis, systemic sclerosis, polyarteritis nodosa,multiple sclerosis and bullous pemphigoid, and additional autoimmunediseases, which can be B-cell (humoral) based or T-cell based, includingCogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis,autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis;(4) cancers or tumors, including alimentary/gastrointestinal tractcancer, colon cancer, liver cancer, skin cancer including mast celltumor and squamous cell carcinoma, breast and mammary cancer, ovariancancer, prostate cancer, lymphoma and leukemia (including but notlimited to acute myelogenous leukemia, chronic myelogenous leukemia,mantle cell lymphoma, NHL B cell lymphomas (e.g. precursor B-ALL,marginal zone B cell lymphoma, chronic lymphocytic leukemia, diffuselarge B cell lymphoma, Burkitt lymphoma, mediastinal large B-celllymphoma), Hodgkin lymphoma, NK and T cell lymphomas; TEL-Syk andITK-Syk fusion driven tumors, myelomas including multiple myeloma,myeloproliferative disorders, kidney cancer, lung cancer, muscle cancer,bone cancer, bladder cancer, brain cancer, melanoma including oral andmetastatic melanoma, Kaposi's sarcoma, proliferative diabeticretinopathy, and angiogenic-associated disorders including solid tumors,and pancreatic cancer; (5) diabetes, including Type I diabetes andcomplications from diabetes; (6) eye diseases, disorders or conditionsincluding autoimmune diseases of the eye, keratoconjunctivitis, vernalconjunctivitis, uveitis including uveitis associated with Behcet'sdisease and lens-induced uveitis, keratitis, herpetic keratitis, conicalkeratitis, corneal epithelial dystrophy, keratoleukoma, ocularpremphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy,Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye),phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy,sympathetic ophthalmitis, allergic conjunctivitis, and ocularneovascularization; (7) intestinal inflammations, allergies orconditions including Crohn's disease and/or ulcerative colitis,inflammatory bowel disease, coeliac diseases, proctitis, eosinophilicgastroenteritis, and mastocytosis; (8) neurodegenerative diseasesincluding motor neuron disease, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, Huntington's disease, cerebralischemia, or neurodegenerative disease caused by traumatic injury,strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injuryin stroke, myocardial ischemia, renal ischemia, heart attacks, cardiachypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia; (9)platelet aggregation and diseases associated with or caused by plateletactivation, such as arteriosclerosis, thrombosis, intimal hyperplasiaand restenosis following vascular injury; (10) conditions associatedwith cardiovascular diseases, including restenosis, acute coronarysyndrome, myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, a thrombotically mediated cerebrovascularsyndrome, embolic stroke, thrombotic stroke, transient ischemic attacks,venous thrombosis, deep venous thrombosis, pulmonary embolus,coagulopathy, disseminated intravascular coagulation, thromboticthrombocytopenic purpura, thromboangiitis obliterans, thrombotic diseaseassociated with heparin-induced thrombocytopenia, thromboticcomplications associated with extracorporeal circulation, thromboticcomplications associated with instrumentation such as cardiac or otherintravascular catheterization, intra-aortic balloon pump, coronary stentor cardiac valve, conditions requiring the fitting of prostheticdevices, and the like; (11) skin diseases, conditions or disordersincluding atopic dermatitis, eczema, psoriasis, scleroderma, pruritusand other pruritic conditions; (12) allergic reactions includinganaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria,angioedema, allergic asthma, or allergic reaction to insect bites, food,drugs, or pollen; (13) transplant rejection, including pancreas islettransplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bonemarrow, cartilage, cornea, heart, intervertebral disc, islet, kidney,limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, smallintestine, or trachea, and xeno transplantation; (14) low grade scarringincluding scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury, andpost-myocardial infarction.

The present disclosure thus provides the use of the compound of formula(I) or a pharmaceutically acceptable salt, a stereoisomer, a solvate, ahydrate, a polymorph, a prodrug or an isotopic variants thereof intherapeutics, especially in the treatment of diseases and disordersmediated by inappropriate BTK activity.

The inappropriate BTK activity referred to herein is any BTK activitythat deviates from the normal BTK activity expected in a particularmammalian subject. Inappropriate BTK activity may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of BTK activity. Such inappropriate activity mayresult then, for example, from overexpression or mutation of the proteinkinase leading to inappropriate or uncontrolled activation.

In a further embodiment, the present disclosure is directed to methodsof regulating, modulating, or inhibiting BTK for the prevention and/ortreatment of disorders related to unregulated or inappropriate BTKactivity.

In a further embodiment said disorder mediated by BTK activity isasthma. In a further embodiment said disorder is rheumatoid arthritis.In yet another embodiment, said disorder is cancer. In a furtherembodiment said disorder is ocular conjunctivitis.

In another embodiment, the present disclosure provides the use of thecompound of formula (I) or a pharmaceutically acceptable salt, astereoisomer, a solvate, a hydrate, a polymorph, a prodrug or anisotopic variants thereof in the manufacture of a medicament fortreating diseases mediated by BTK activity.

A further aspect of the disclosure resides in the use of a compound offormula (I) or a pharmaceutically acceptable salt, a stereoisomer, asolvate, a hydrate, a polymorph, a prodrug or an isotopic variantsthereof for the manufacture of a medicament to be used for the treatmentof BTK-mediated diseases.

A further aspect of the disclosure resides in the use of a compound offormula (I) or a pharmaceutically acceptable salt, a stereoisomer, asolvate, a hydrate, a polymorph, a prodrug or an isotopic variantsthereof for the manufacture of a medicament to be used for the treatmentof chronic B cell disorders in which T cells play a prominent role.

In yet another aspect the disclosure resides in the use of a compound offormula (I) or a pharmaceutically acceptable salt, a stereoisomer, asolvate, a hydrate, a polymorph, a prodrug or an isotopic variantsthereof for the manufacture of a medicament to be used for the treatmentof BTK-mediated diseases. These BTK-mediated diseases include, but arenot limited to, B cell lymphomas resulting from chronic active B cellreceptor signaling.

Thus, the compounds disclosed herein may be used to treat or preventdiseases such as Bruton's Tyrosine Kinase (BTK) mediated diseases. BTKmediated diseases as used herein, mean any disease state or otherdeleterious condition in which B cells, mast cells, myeloid cells orosteoclasts play a central role. These diseases include but are notlimited to, immune, autoimmune and inflammatory diseases, allergies,infectious diseases, bone resorption disorders and proliferativediseases.

Immune, autoimmune and inflammatory diseases that may be treated orprevented with the compounds disclosed herein include rheumatic diseases(e.g. rheumatoid arthritis, psoriatic arthritis, infectious arthritis,progressive chronic arthritis, deforming arthritis, osteoarthritis,traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis,acute synovitis and spondylitis), glomerulonephritis (with or withoutnephrotic syndrome), Goodpasture's syndrome, (and associatedglomerulonephritis and pulmonary hemorrhage), atherosclerosis,autoimmune hematologic disorders (e.g. hemolytic anemia, aplasic anemia,idiopathic thrombocytopenia, chronic idiopathic thrombocytopenic purpura(ITP), and neutropenia), autoimmune gastritis, and autoimmuneinflammatory bowel diseases (e.g. ulcerative colitis and Crohn'sdisease), irritable bowel syndrome, host versus graft disease, allograftrejection, chronic thyroiditis, Graves' disease, Sjorgren's disease,scleroderma, diabetes (type I and type II), active hepatitis (acute andchronic), pancreatitis, primary billiary cirrhosis, myasthenia gravis,multiple sclerosis, systemic lupus erythematosis, psoriasis, atopicdermatitis, dermatomyositis, contact dermatitis, eczema, skin sunburns,vasculitis (e.g. Behcet's disease), ANCA-associated and othervasculitudes, chronic renal insufficiency, Stevens-Johnson syndrome,inflammatory pain, idiopathic sprue, cachexia, sarcoidosis,Guillain-Barre syndrome, uveitis, conjunctivitis, kerato conjunctivitis,otitis media, periodontal disease, Addison's disease, Parkinson'sdisease, Alzheimer's disease, diabetes, septic shock, myasthenia gravis,pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis,sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonaryemphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonarydisease (e.g. chronic obstructive pulmonary disease) and otherinflammatory or obstructive disease on airways.

Allergies that may be treated or prevented include, among others,allergies to foods, food additives, insect poisons, dust mites, pollen,animal materials and contact allergens, type I hypersensitivity allergicasthma, allergic rhinitis, allergic conjunctivitis.

Infectious diseases that may be treated or prevented include, amongothers, sepsis, septic shock, endotoxic shock, sepsis by Gram-negativebacteria, shigellosis, meningitis, cerebral malaria, pneumonia,tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitisB and hepatitis C), HIV infection, retinitis caused by cytomegalovirus,influenza, herpes, treatment of infections associated with severe burns,myalgias caused by infections, cachexia secondary to infections, andveterinary viral infections such as lentivirus, caprine arthritic virus,visna-maedi virus, feline immunodeficiency virus, bovineimmunodeficiency virus or canine immunodeficiency virus.

Bone resorption disorders that may be treated or prevented include,among others, osteoporosis, osteoarthritis, traumatic arthritis, goutyarthritis and bone disorders related with multiple myeloma.

Proliferative diseases that may be treated or prevented include, amongothers, non-Hodgkin lymphoma (in particular the subtypes diffuse largeB-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)), B cell chroniclymphocytic leukemia and acute lymphoblastic leukemia (ALL) with matureB cell, ALL in particular.

In particular the compounds of formula (I) or pharmaceuticallyacceptable salts may be used for the treatment of B cell lymphomasresulting from chronic active B cell receptor signaling.

Included herein are methods of treatment and/or pharmaceuticalcompositions in which at least one compound of formula (I) or apharmaceutically acceptable salt thereof is administered in combinationwith at least one other active agent. The other active agent is ananti-inflammatory agent, an immunosuppressant agent, or achemotherapeutic agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The disclosure also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the disclosure pertain to combinations in which atleast one anti-inflammatory agent is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the disclosure pertain to combinations inwhich at least one active agent is an immunosuppressant agent, such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

It has also been discovered that BTK inhibitors are useful aschemosensitizing agents, and, thus, are useful in combination with otherchemotherapeutic agents, in particular, drugs that induce apoptosis.Examples of other chemotherapeutic agents that can be used incombination with chemosensitizing BTK inhibitors include topoisomerase Iinhibitors (camptothecin or topotecan), topoisomerase II inhibitors(e.g. daunomycin and etoposide), alkylating agents (e.g.cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g.taxol and vinblastine), and biological agents (e.g. antibodies such asanti CD20 antibody, IDEC 8, immunotoxins, and cytokines).

In another embodiment, the present disclosure provides a method oftreating a mammal having a disease mediated by BTK activity, the methodcomprising: administering to the mammal an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt, a solvateor a physiologically functional derivative thereof.

An effective amount of a compound disclosed herein will generally beadministered in a single or multiple doses at an average daily dose offrom 0.01 mg to 50 mg of compound per kilogram of patient body weight,preferably from 0.1 mg to 25 mg of compound per kilogram of patient bodyweight. In general, the compounds disclosed herein may be administeredto a patient in need of such treatment in a daily dosage range of fromabout 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000mg. For example, the daily dose per patient can be 10, 20, 30, 40, 50,60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800,900 or 1000 mg. It can be administered one or more times daily, weekly(or several days apart) or on an intermittent schedule. For example, thecompound can be administered one or more times per day on a weekly basis(e.g., every Monday), continually or for several weeks, such as 4-10weeks. Alternatively, the administration may be continued for severaldays (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) withoutadministration of the compound, and the cycle may be repeatedindefinitely or repeated for a given number of times, such as 4-10.Cycles. For example, the compounds disclosed herein may be administereddaily for 5 days, then intermittently for 9 days, then administereddaily for 5 days, then intermittent for 9 days, and so on, and the cycleis repeated indefinitely or repeated 4-10 times.

Combination in Therapy

Compounds disclosed herein, and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of BTKmediated diseases and conditions associated with inappropriate BTKactivity. Combination therapies according to the present disclosure thuscomprise the administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other pharmaceutically active agent. The compound(s) of formula (I)and the other pharmaceutically active agent(s) may be administeredtogether or separately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

For the treatment of the inflammatory diseases, rheumatoid arthritis,psoriasis, inflammatory bowel disease, COPD, asthma and allergicrhinitis a compound of formula (I) may be combined with one or moreother active agents such as: (1) TNF-α inhibitors such as infliximab(Remicade®), etanercept (Enbrel®), adalimumab (Humira®), certolizumabpegol (Cimzia®), and golimumab (Simponi®); (2) nonselective COX-1/COX-2inhibitors (such as piroxicam, diclofenac, propionic acids such asnaproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamatessuch as mefenamic acid, indomethacin, sulindac, etodolac, azapropazone,pyrazolones such as phenylbutazone, salicylates such as aspirin); (3)COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxiband etoricoxib); (4) other agents for treatment of rheumatoid arthritisincluding methotrexate, leflunomide, sulfasalazine, azathioprine,cyclosporin, tacrolimus, penicillamine, bucillamine, actarit,mizoribine, lobenzarit, ciclesonide, hydroxychloroquine,d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold,cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig ormimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase(5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonistsuch as zileuton; (6) LTD4 receptor antagonist such as zafirlukast,montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast,cilomilast, AWD-12-281 (Elbion), and PD-168787 (Pfizer); (8)antihistaminic HI receptor antagonists such as cetirizine,levocetirizine, loratadine, desloratadine, fexofenadine, astemizole,azelastine, levocabastine, olopatidine, methapyrilene andchlorpheniramine; (9) α1- and α2-adrenoceptor agonist vasoconstrictorsympathomimetic agent, such as propylhexedrine, phenylephrine,phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride;(10) anticholinergic agents such as ipratropium bromide, tiotropiumbromide, oxitropium bromide, aclindinium bromide, glycopyrrolate,(R,R)-glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptoragonists such as metaproterenol, isoproterenol, isoprenaline, albuterol,formoterol (particularly the fumarate salt), salmeterol (particularlythe xinafoate salt), terbutaline, orciprenaline, bitolterol mesylate,fenoterol, and pirbuterol, or methylxanthanines including theophyllineand aminophylline, sodium cromoglycate; (12) insulin-like growth factortype I (IGF-1) mimetic; (13) glucocorticosteroids, especially inhaledglucocorticoid with reduced systemic side effects, such as prednisone,prednisolone, flunisolide, triamcinolone acetonide, beclomethasonedipropionate, budesonide, fluticasone propionate, ciclesonide andmometasone furoate; (14) kinase inhibitors such as inhibitors of theJanus Kinases (JAK1 and/or JAK2 and or JAK3 and/or TYK2), p38 MAPK andIKK2; (15) B-cell targeting biologies such as rituximab (Rituxan®); (16)selective costimulation modulators such as abatacept (Orencia); (17)interleukin inhibitors, such as IL-1 inhibitor anakinra (Kineret) andIL-6 inhibitor tocilizumab (Actemra).

The present disclosure also provides for “triple combination” therapy,comprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with beta2-adrenoreceptor agonist and ananti-inflammatory corticosteroid. Preferably this combination is fortreatment and/or prophylaxis of asthma, COPD or allergic rhinitis.

For the treatment of cancer a compound of formula (I) may be combinedwith one or more of an anticancer agents. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Suchanti-cancer agents include, but are not limited to, the following: (1)estrogen receptor modulator such as diethylstibestral, tamoxifen,raloxifene, idoxifene, LY353381, LY117081, toremifene, fluoxymestero,and SH646; (2) other hormonal agents including aromatase inhibitors(e.g., aminoglutethimide, tetrazole anastrozole, letrozole andexemestane), luteinizing hormone release hormone (LHRH) analogues,ketoconazole, goserelin acetate, leuprolide, megestrol acetate andmifepristone; (3) androgen receptor modulator such as finasteride andother 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate; (4) retinoid receptor modulator suchas bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide;(5) antiproliferative agent such as antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and FNX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,

N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradeca-dienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, aminopterin,5-flurouracil, floxuridine, methotrexate, leucovarin, hydroxyurea,thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin,fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine,alanosine, swainsonine, lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) prenyl-proteintransferase inhibitor including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase); (7) HMG-CoA reductase inhibitor such as lovastatin,simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin;(8) angiogenesis inhibitor such as inhibitors of the tyrosine kinasereceptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors ofepidermal-derived, fibroblast-derived, or platelet derived growthfactors, MMP (matrix metalloprotease) inhibitors, integrin blockers,interferon-α, interleukin-12, erythropoietin (epoietin-α),granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF(sargramostim), pentosan polysulfate, cyclooxygenase inhibitors,steroidal anti-inflammatories, carboxyamidotriazole, combretastatin A-4,squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,angiostatin, troponin-1, angiotensin II antagonists, heparin,carboxypeptidase U inhibitors, and antibodies to VEGF, endostatin,ukrain, ranpirnase, IM862, acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate, and3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416); (9) PPAR-γagonists, PPAR-δ agonists, thiazolidinediones (such as DRF2725, CS-011,troglitazone, rosiglitazone, and pioglitazone), fenofibrate,gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555,GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570,PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and(2R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. Nos. 60/235,708 and 60/244,697); (9)inhibitor of inherent multidrug resistance including inhibitors ofp-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922,VX853 and PSC833 (valspodar); (10) inhibitor of cell proliferation andsurvival signaling such as inhibitors of EGFR (for example gefitinib,erlotinib, icotinib and Osimertinib (AZD9291)), inhibitors of ERB-2 (forexample trastuzumab), inhibitors of IGF1R such as MK-0646 (dalotuzumab),inhibitors of CD20 (rituximab), inhibitors of cytokine receptors,inhibitors of MET, inhibitors of PI3K family kinase (for exampleLY294002), serine/threonine kinases (including but not limited toinhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO02/083138), inhibitors of Raf kinase (for example BAY-43-9006),inhibitors of MEK (for example CI-1040 and PD-098059) and inhibitors ofmTOR (for example Wyeth CCI-779 and Ariad AP23573); (11) abisphosphonate such as etidronate, pamidronate, alendronate,risedronate, zoledronate, ibandronate, incadronate or cimadronate,clodronate, EB-1053, minodronate, neridronate, piridronate andtiludronate; (12) γ-secretase inhibitors, (13) agents that interferewith receptor tyrosine kinases (RTKs) including inhibitors of c-Kit,Eph, PDGF, Flt3 and c-Met; (14) agent that interferes with a cell cyclecheckpoint including inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand CDK and CDC kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032;(15) BTK inhibitors such as PCI32765, AVL-292 and AVL-101; (16) PARPinhibitors including iniparib, olaparib, AG014699, ABT888 and MK4827;(16) ERK inhibitors; (17) mTOR inhibitors such as sirolimus,ridaforolimus, temsirolimus, everolimus; (18) cytotoxic/cytostaticagents.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine,melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine,streptozocin, tasonermin, lonidamine, carboplatin, altretamine,dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzyl guanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin,mitomycin C, dactinomycin, plicatomycin, bisantrene, mitoxantrone,pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude vincristine, vinblastine, vindesine, vinzolidine, vinorelbine,vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate,auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS 188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, lurtotecan,7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100,BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-T-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,

N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]-formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98,valproic acid and scriptaid.

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R₁. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine, aminopterin, 5-flurouracil,floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Non-limiting examples of suitable agents used in cancer therapy that maybe combined with compounds of formula (I) include, but are not limitedto, abarelix; aldesleukin; alemtuzumab; alitretinoin; allopurinol;altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase;azacitidine; bendamustine; bevacuzimab; bexarotene; bleomycin;bortezomib; busulfan; calusterone; capecitabine; carboplatin;carmustine; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine;cyclophosphamide; cytarabine; dacarbazine; dactinomycin, actinomycin D;dalteparin; darbepoetin alfa; dasatinib; daunorubicin; degarelix;denileukin diftitox; dexrazoxane; docetaxel; doxorubicin; dromostanolonepropionate; eculizumab; Elliott's B Solution; eltrombopag; epirubicin;epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide;everolimus; exemestane; filgrastim; floxuridine; fludarabine;fluorouracil; fulvestrant; gefitinib; Tarceva; Orsiro; gemcitabine;gemtuzumab ozogamicin; goserelin acetate; histrelin acetate;hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinibmesylate; interferon α-2a; interferon α-2b; irinotecan; ixabepilone;lapatinib; lenalidomide; letrozole; leucovorin; leuprolide acetate;levamisole; lomustine; meclorethamine, nitrogen mustard; megestrolacetate; melphalan, L-PAM; mercaptopurine; mesna; methotrexate;methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolonephenpropionate; nelarabine; nilotinib; Nofetumomab; ofatumumab;oprelvekin; oxaliplatin; paclitaxel; palifermin; pamidronat;panitumumab; pazopanib; pegademase; pegaspargase; Pegfilgrastim;pemetrexed disodium; pentostatin; pipobroman; plerixafor; plicamycin,mithramycin); porfimer sodium; pralatrexate; procarbazine; quinacrine;Rasburicase; raloxifene hydrochloride; Rituximab; romidepsin;romiplostim; sargramostim; sargramostim; satraplatin; sorafenib;streptozocin; sunitinib maleate; tamoxifen; temozolomide; temsirolimus;teniposide; testolactone; thioguanine; thiotepa; topotecan; toremifene;tositumomab; trastuzumab; tretinoin; uracil mustard; valrubicin;vinblastine; vincristine; vinorelbine; vorinostat; and zoledronate.

It will be apparent to those skilled in the art that, where appropriate,the other therapeutic component or ingredients may be used in the formof a salt (e.g., an alkali metal salt or amine salt or an acid additionsalt), or a prodrug, or an ester (e.g., an ester of lower alkyl group),or solvates (e.g., hydrates), to optimize the activity and/or stabilityand/or physical properties (e.g., solubility) of the therapeuticcomponent. It is also clear that the therapeutic ingredients can be usedin optically pure form, where appropriate.

The above combination may conveniently be used in the form of apharmaceutical composition, and thus a pharmaceutical compositioncomprising the above combination and a pharmaceutically acceptablediluent or carrier represents a further aspect of the presentdisclosure. These combinations are particularly useful for respiratorydiseases and are suitable for inhalation or intranasal delivery.

The individual compound in the combination may be administeredsequentially or simultaneously in separate or combined pharmaceuticalcompositions. Preferably, each compound is administered simultaneouslyin the form of a combined pharmaceutical composition. Suitable dosagesof known therapeutic agents are readily apparent to those skilled in theart.

EXAMPLES

The following examples are provided to provide those skilled in the artwith a complete disclosure and description of how to carry out themethods, and prepare and evaluate the compounds disclosed herein, whichare only for illustrative purpose and not constitute any limitation ofthe scope of the invention.

Synthetic Method

The compounds of the present disclosure can be prepared according toconventional methods in the art and using suitable reagents, startingmaterials, and purification methods known to those skilled in the art.

The preparation of the compounds of the present disclosure is morespecifically described below, but these specific methods do notconstitute any limitation to the present disclosure. The compounds ofthe present disclosure may also be conveniently prepared by combiningvarious synthetic methods described in the specification or known in theart, and such combinations are readily available to those skilled in theart to which the present disclosure pertains.

Usually, in the preparation, each reaction is usually carried out in aninert solvent at room temperature to reflux temperature (e.g., 0° C. to100° C., preferably 0° C. to 80° C.). The reaction time is usually from0.1 to 60 hours, preferably from 0.5 to 24 hours.

Example 1 Preparation of1-(3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)prop-2-en-1-one(Compound 14)

The specific synthetic steps are as follows:

Step 1. Synthesis of (E)-tert-butyl3-(cyanomethylene)piperidin-1-carboxylate (Compound 3)

Under nitrogen protection, sodium hydride (NaH, 0.19 g, 7.8 mmol) wasadded to 10 mL tetrahydrofuran, which was cooled to 0° C. with an icebath, diethyl (cyanomethyl)phosphonate (compound 2, 1.38 g, 7.8 mmol)was added dropwise, and stirred for 10 minutes after the complete ofaddition. Then N-tert-butoxycarbonyl-3-piperidinone (compound 1, 1.7 g,8.5 mmol) in 10 mL tetrahydrofuran (THF) was added dropwise to thesolution, ice bath was removed after the complete of addition, and thereaction was reacted at room temperature overnight. To the reactionmixture were added 30 mL water and 30 mL ethyl acetate, stirred for 5minutes, and the layers were separated after standing. The organicelayer was washed with 10 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford 1.4 g of alight yellow oil, yield was 74%. LC-MS(APCI): m/z=223(M+1)⁺.

Step 2. Synthesis of tert-butyl 3-(cyanomethyl)piperidin-1-carboxylate(Compound 4)

(E)-tert-butyl 3-(cyanomethylene)piperidin-1-carboxylate (1.4 g, 6.3mmol) was dissolved in 20 mL anhydrous ethanol, to which 150 mg 10% Pd/Cwas added, the atmosphere was replaced with hydrogen gas for threetimes, the mixture was stirred under 1 atmospheric pressure of hydrogengas at 50° C. overnight. Pd/C was filtered off after the reaction wascomplete, the filtrate was concentrated, and separated by silica gelcolumn to afford 1.2 g of a light yellow oil, yield was 85%.LC-MS(APCI): m/z=225(M+1)⁺.

Step 3. Synthesis of tert-butyl3-(1-cyano-2-oxoethyl)piperidin-1-carboxylate (Compound 5)

Tert-butyl 3-(cyanomethyl)piperidin-1-carboxylate (1.2 g, 5.4 mmol) wasdissolved in 10 mL tetrahydrofuran, which was cooled to −78° C., asolution of lithium diisopropylamide (LDA, 0.3 mg, 2.7 mmol) intetrahydrofuran (2M, 2.7 mL) was slowly added dropwise, and stirred for10 minutes after the complete of addition. Then a pre-colded solution ofethyl formate (0.42 g, 5.6 mmol) in 10 mL tetrahydrofuran was addeddropwise. After the addition was over, the reaction was reacted at −78°C. for 0.5 hour, then ice bath was removed, and the reaction was warmedto room temperature naturally and reacted overnight. The reactionmixture was adjusted with 1N hydrochloric acid to pH=3, then extractedwith ethyl acetate, and the organic phase was washed with 15 mL brine,dried over anhydrous sodium sulfate, concentrated, and purified bycolumn chromatography to afford 0.9 g of a light yellow oil, yield was66.6%. LC-MS(APCI): m/z=253(M+1)⁺.

Step 4. Synthesis of 2-((4-phenoxyphenyl)amino)acetonitrile (Compound 8)

4-phenoxyaniline (compound 6, 1.85 g, 10 mmol), bromoacetonitrile(compound 7, 1.56 g, 13 mmol) and triethylamine (TEA, 3 mL, 22 mmol)were dissolved in 50 mL tetrahydrofuran, which was reacted at 80° C.overnight. The temperature was cooled to room temperature after thereaction was complete, concentrated to dry under reduced pressure, 20 mLsaturated solution of ammonium chloride and 30 mL ethyl acetate wereadded, the layers were separated while stirring, the organic phase waswashed with 10 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford 1.9 g of alight yellow solid, yield was 85%. LC-MS(APCI): m/z=225(M+1)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.36 (ddd, J=4.9, 2.0, 0.9 Hz, 1H),8.17 (dt, J=8.4, 1.1 Hz, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.80 (ddd, J=8.7,7.4, 2.0 Hz, 1H), 7.12 (ddd, J=7.3, 4.8, 1.1 Hz, 1H), 6.87 (t, J=6.6 Hz,1H), 6.78 (d, J=8.8 Hz, 2H), 4.37 (d, J=6.6 Hz, 2H).

Step 5. Synthesis of (Z)-tert-butyl3-(1-cyano-2-((cyanomethyl)(4-phenoxyphenyl)amino)vinyl)piperidin-1-carboxylate(Compound 9)

2-((4-phenoxyphenyl)amino)acetonitrile (compound 8, 0.67 g, 3 mmol),tert-butyl 3-(1-cyano-2-oxoethyl)piperidin-1-carboxylate (compound 5,0.9 g, 3.6 mmol) and p-toluene sulfonic acid (57 mg, 0.3 mmol) weredissolved in 20 mL toluene. Water separator was set, and the reactionwas refluxed overnight. The temperature was cooled to room temperatureafter the reaction was complete, concentrated to dry under reducedpressure, 10 mL saturated solution of sodium bicarbonate was added,stirred for 5 minutes, extracted with ethyl acetate, the organic phasewas washed with 15 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford lightyellow solid 0.96 g, yield was 70%. LC-MS(APCI): m/z=459(M+1)⁺.

Step 6. Synthesis of tert-butyl3-(4-amino-5-cyano-1-(4-phenoxyphenyl)-1H-pyrrol-3-yl)piperidin-1-carboxylate(Compound 10)

(Z)-tert-butyl

3-(1-cyano-2-((cyanomethyl)(4-phenoxyphenyl)amino)vinyl)piperidin-1-carboxylate(compound 9, 0.96 g, 2.1 mmol) was dissolved in 10 mL tert-butylalcohol, potassium tert-butoxide (t-BuOK, 0.55 g, 4.9 mmol) was added inportions under stirring, and the reaction was reacted at 80° C. for 2hours after the addition was complete. The reaction mixture was cooledto room temperature, poured into 20 mL 10% hydrochloric acid, stirredfor 5 minutes, extracted with ethyl acetate, the organic phase waswashed with 15 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford 0.63 g ofa red-brown solid, yield was 63%. LC-MS(APCI): m/z=459(M+1)⁺.

Step 7. Synthesis of tert-butyl3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-carboxylate(Compound 11)

Tert-butyl

3-(4-amino-5-cyano-1-(4-phenoxyphenyl)-1H-pyrrol-3-yl)piperidin-1-carboxylate(0.31 g, 0.7 mmol) was dissolved in 10 mL methanol, and formamidineacetate (0.55 g, 5.5 mmol) was added, and the reaction was refluxedovernight. The reaction mixture was cooled to room temperature,concentrated to dry under reduced pressure, 20 mL saturated solution ofsodium bicarbonate was added, stirred for 5 minutes, extracted withethyl acetate, the organic phase was washed with 15 mL brine, dried overanhydrous sodium sulfate, concentrated, and purified by columnchromatography to afford 0.26 g of a light yellow solid, yield was 80%.LC-MS(APCI): m/z=486(M+1)⁺.

Step 8. Synthesis of5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 12)

Tert-butyl

3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-carboxylate(0.26 g, 0.57 mmol) was dissolved in 10 mL dichloromethane, 4 mLtrifluoroacetic acid was added, and stirred at room temperature for 1hour. After being concentrated to dry under reduced pressure, 20 mLdichloromethane and 15 mL saturated solution of sodium bicarbonate wereadded, stirred for 5 minutes, the layers were separated, the organicphase was washed with 5 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford 186 mg ofa white solid, yield was 90%. LC-MS(APCI): m/z=386(M+1)⁺.

Step 9. Synthesis of1-(3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)prop-2-en-1-one(Compound 14)

5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(180 mg, 0.47 mmol) was dissolved in 10 mL dichloromethane, which wascooled to −15° C., acryloyl chloride (compound 13, 42 mg, 0.47 mmol) wasslowly added dropwise, and after the addition was complete, the reactionwas stirred for 10 minutes. Ice bath was removed, then reacted for 1hour. To the reaction mixture were added 10 mL water and 10 mLdichloromethane, the layers were separated while stirring, the organicphase was washed with 5 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford 140 mg ofa white solid, yield was 70%. LC-MS(APCI): m/z=440(M+1)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.22 (d, J=6.9 Hz, 1H), 7.52 (s, 1H), 7.48-7.39 (m, 4H),7.21 (d, J=7.4 Hz, 1H), 7.18-7.10 (m, 4H), 6.92-6.76 (m, 1H), 6.10 (dd,J=16.7, 2.4 Hz, 1H), 5.88 (s, 2H), 5.66 (d, J=10.5 Hz, 1H), 4.43-4.31(m, 1H), 3.11 (t, J=12.3 Hz, 0.5H), 2.95 (t, J=11.2 Hz, 1H), 2.76 (t,J=12.3 Hz, 0.5H), 2.17-2.07 (m, 1H), 2.04-1.94 (m, 2H), 1.78 (d, J=13.5Hz, 1H), 1.56-1.41 (m, 2H).

Example 2 Preparation of1-(3-(7-amino-1-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one (Compound 23)

The specific synthetic steps are as follows:

Step 1. Synthesis of (Z)-tert-butyl3-(1-cyano-2-methoxy-2-oxoethylene)piperidin-1-carboxylate (Compound 16)

N-tert-butoxycarbonyl-3-piperidinone (1.99 g, 10 mmol), cyanoethylacetate (0.99 g, 1 mmol) and ammonium acetate (100 mg, 1.3 mmol) wereadded to 10 mL toluene, 0.2 mL acetic acid was added dropwise, waterseparator was set, and the reaction was refluxed overnight. Thetemperature was cooled to room temperature after the reaction wascomplete, the reaction was concentrated to dry under reduced pressure,20 mL water and 20 mL ethyl acetate were added, the layers wereseparated while stirring, the organic phase was washed with 10 mL brine,dried over anhydrous sodium sulfate, concentrated, and purified bycolumn chromatography to afford 2.2 g of a light yellow oil, yield was80%. LC-MS(APCI): m/z=281(M+1)⁺.

Step 2. Synthesis of tert-butyl3-(1-cyano-2-methoxy-2-oxoethyl)piperidin-1-carboxylate (Compound 17)

(Z)-tert-butyl3-(1-cyano-2-methoxy-2-oxoethylene)piperidin-1-carboxylate (2.2 g, 7.8mmol) was dissolved in 20 mL anhydrous ethanol, 200 mg 10% Pd/C wasadded, the atmosphere was replaced with hydrogen gas for three times,and the mixture was stirred under 1 atmospheric pressure of hydrogen gasat 50° C. overnight. Pd/C was filtered off after the reaction wascomplete, filtrate was concentrated, and separated by silica gel columnto afford 1.34 g of a light yellow oil, yield was 61%. LC-MS(APCI):m/z=283(M+1)⁺.

Step 3. Synthesis of (E)-tert-butyl3-(1-cyano-2-methoxy-2-oxo-1-((4-phenoxyphenyl)diazenyl)ethyl)piperidin-1-carboxylate(Compound 18)

4-methoxyaniline (1.57 g, 8.5 mmol) was dissolved in 20 mL 1Nhydrochloric acid, 1M aqueous solution of sodium nitrite (0.58 g, 8.5mmol) was added dropwise at room temperature, the reaction mixture wasstirred at room temperature for 1 hour after the addition was complete.Under an ice bath, the above reaction mixture was slowly added totert-butyl 3-(1-cyano-2-methoxy-2-oxoethyl)piperidin-1-carboxylate (1.2g, 4.2 mmol) in ethanol (6 mL)-water (80 mL), adjusted with sodiumacetate to pH=7, and the reaction mixture was stirred at 0° C. for 3hours, then warmed to room temperature and the mixture was stirredovernight. To the reaction mixture was added 30 mL saturated solution ofammonium chloride and 50 mL ethyl acetate, the layers were separatedwhile stirring, the organic phase was washed with 10 mL brine, driedover anhydrous sodium sulfate, concentrated, and purified by columnchromatography to afford 1.02 g of a light yellow oil, yield was 50%.LC-MS(APCI): m/z=479(M+1)⁺.

Step 4. Synthesis of (Z)-tert-butyl3-(cyano(2-(4-phenoxyphenyl)hydrazono)methyl)piperidin-1-carboxylate(Compound 19)

(E)-tert-butyl

3-(1-cyano-2-methoxy-2-oxo-1-((4-phenoxyphenyl)diazenyl)ethyl)piperidin-1-carboxylate(1.0 g, 2.1 mmol) was dissolved in 20 mL tetrahydrofuran, cooled to 0°C. in an ice bath, 10N aqueous solution of sodium hydroxide (5 mL) wasadded, and stirred at room temperature for 1 hour. 30 mL saturatedsolution of ammonium chloride and 50 mL ethyl acetate were added, thelayers were separated while stirring, the organic phase was washed with10 mL brine, dried over anhydrous sodium sulfate, concentrated, andpurified by column chromatography to afford 0.66 g of a light yellowoil, yield was 75%. LC-MS(APCI): m/z=421(M+1)⁺.

Step 5. Synthesis of tert-butyl3-(4-amino-5-cyano-1-(4-phenoxyphenyl)-1H-pyrazol-3-yl)piperidin-1-carboxylate(Compound 20)

(Z)-tert-butyl

3-(cyano(2-(4-phenoxyphenyl)hydrazono)methyl)piperidin-1-carboxylate(0.66 g, 1.6 mmol) and bromoacetonitrile (0.13 mL, 3.4 mmol) weredissolved in 10 mL tert-butyl alcohol, potassium tert-butoxide (0.54 g,4.8 mmol) was added in portions at room temperature, and stirred at roomtemperature for 2 hours. 20 mL water and 40 mL ethyl acetate were added,the layers were separated while stirring, the organic phase was washedwith 10 mL brine, dried over anhydrous sodium sulfate, concentrated, andpurified by column chromatography to afford 0.5 g of a light yellow oil,yield was 70%. LC-MS(APCI): m/z=460(M+1)⁺.

Step 6. Synthesis of tert-butyl3-(7-amino-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-carboxylate(Compound 21)

Tert-butyl

3-(4-amino-5-cyano-1-(4-phenoxyphenyl)-1H-pyrazol-3-yl)piperidin-1-carboxylate(0.25 g, 0.55 mmol) was dissolved in 10 mL methanol, formamidine acetate(0.45 g, 4.4 mmol) was added, and the reaction was refluxed overnight.The reaction mixture was cooled to room temperature, concentrated to dryunder reduced pressure, 20 mL saturated solution of sodium bicarbonatewas added, and stirred for 5 minutes, extracted with ethyl acetate, theorganic phase was washed with 10 mL brine, dried over anhydrous sodiumsulfate, concentrated, and purified by column chromatography to afford210 mg of a light yellow solid, yield was 80%. LC-MS(APCI):m/z=487(M+1)⁺.

Step 7. Synthesis of1-(4-phenoxyphenyl)-3-(piperidin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine(Compound 22)

Tert-butyl

3-(7-amino-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-carboxylate(200 mg, 0.41 mmol) was dissolved in 10 mL dichloromethane, 4 mLtrifluoroacetic acid was added, and stirred at room temperature for 1hour. The reaction was concentrated to dry under reduced pressure, 20 mLdichloromethane and 15 mL saturated solution of sodium bicarbonate wereadded, stirred for 5 minutes, the layers were separated, the organicphase was washed with 5 mL brine, dried over anhydrous sodium sulfate,concentrated, and purified by column chromatography to afford 140 mg ofa white solid, yield was 90%. LC-MS(APCI): m/z=387(M+1)⁺.

Step 8. Synthesis of1-(3-(7-amino-1-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one (Compound 23)

1-(4-phenoxyphenyl)-3-(piperidin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine(0.14 g, 0.36 mmol) was dissolved in 10 mL dichloromethane, cooled to−15° C., acryloyl chloride (32 mg, 0.36 mmol) was slowly added dropwise,and stirred for 10 minutes after the addition was complete. The ice bathwas removed, and the reaction was continued for 1 hour. To the reactionmixture were added 10 mL water and 10 mL dichloromethane, the layerswere separated while stirring, the organic phase was washed with 5 mLbrine, dried over anhydrous sodium sulfate, concentrated, and purifiedby column chromatography to afford 116 mg of a white solid, yield was73%. LC-MS(APCI): m/z=441(M+1)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d,J=11.8 Hz, 1H), 7.65-7.32 (m, 4H), 7.24-6.97 (m, 5H), 6.65 (dd, J=16.7,10.3 Hz, 1H), 6.39-6.18 (m, 1H), 5.65 (dd, J=25.0, 10.8 Hz, 1H), 5.30(s, 2H), 4.42-4.21 (m, 1H), 3.40 (d, J=10.8 Hz, 1H), 3.24 (dt, J=22.3,12.2 Hz, 1H), 3.05-2.76 (m, 1H), 2.33 (d, J=13.7 Hz, 1H), 2.22-1.98 (m,2H), 1.98-1.87 (m, 1H), 1.70 (d, J=13.2 Hz, 1H).

Example 3 Preparation of(S)-1-(3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)prop-2-en-1-one(Compound 24)

Compound 24 was prepared according to the method of Example 1, and wasobtained by chiral column separation.

Example 4 Preparation of(R)-1-(3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)prop-2-en-1-one(Compound 25)

Compound 25 was prepared according to the method of Example 1, and wasobtained by chiral column separation.

Example 5 Preparation of(R)-1-(3-(7-amino-1-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one(Compound 26)

Compound 26 was prepared according to the method of Example 2, and wasobtained by chiral column separation.

Example 6 Preparation of(S)-1-(3-(7-amino-1-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one(Compound 27)

Compound 27 was prepared according to the method of Example 2, and wasobtained by chiral column separation.

Example 7 Preparation of(S)-1-(3-(8-amino-1-(4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one(Compound 38)

Step 1. Synthesis of (3-chloropyrazin-2-yl)methylamine (Compound 29)

2-cyano-3-chloropyrazine (0.8 g, 5.8 mmol) and Raney-Ni (0.3 g) wereadded to 10 mL glacial acetic acid, the atmosphere was replaced withhydrogen gas for three times, the mixture was stirred under 3atmospheric pressure of hydrogen gas at 50° C. overnight. The reactionwas filtered after the reaction was complete, filtrate was concentrated,the residue was dissolved in ethyl acetate, washed with saturatedsolution of sodium bicarbonate, dried over anhydrous sodium sulfate,concentrated, and separated by silica gel column to afford 0.5 g of alight yellow oil, yield was 60%. LC-MS(APCI): m/z=144(M+1)⁺.

Step 2. Synthesis of (R)-benzyl3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)piperidin-1-carboxylate(Compound 31)

(3-chloropyrazin-2-yl)methylamine (0.3 g, 2.1 mmol),(R)-piperidin-1,3-dicarboxylate 1-benzyl (compound 30, 0.55 g, 2.1 mmol)and triethylamine(0.42 g, 4.2 mmol) were dissolved in 10 mLdichloromethane, under an ice bath2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HATU, 0.84 g, 2.2 mmol) was added, and reacted at 0° C. for 1 hour. Thereaction was warmed to room temperature naturally and reacted overnight.After the reaction was complete, the reaction mixture was washedsequentially with 0.1N hydrochloric acid, 5% NaHCO₃ and brine. Theorganic phase was dried over anhydrous sodium sulfate, concentrated, andseparated by silica gel column to afford 0.5 g of a light yellow oil,yield was 62%. LC-MS(APCI): m/z=389(M+1)⁺.

Step 3. Synthesis of (R)-benzyl3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate (Compound32)

(R)-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)piperidin-1-carboxylate(0.49 g, 1.3 mmol) was dissolved in 10 mL anhydrous acetonitrile,phosphorus oxychloride (0.8 g, 5.2 mmol) was added, and the reaction washeated to 60° C. and reacted overnight. The solvent was evaporated afterthe reaction was complete, the residue was slowly added to ice-water,extracted with ethyl acetate (10 mL*3), the organic phase was washedwith 10 mL brine, dried over anhydrous sodium sulfate, concentrated, andseparated by silica gel column to afford 0.37 g of a light yellow solid,yield was 80%. LC-MS(APCI): m/z=371(M+1)⁺.

Step 4. Synthesis of (R)-benzyl3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(Compound 33)

(R)-benzyl 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(0.37 g, 1.0 mmol) was dissolved in 10 mL DMF, N-bromosuccinimide (NBS,0.21 g, 1.2 mmol) was added in portions under an ice bath, the reactionwas warmed to room temperature naturally and reacted overnight. Afterthe reaction was complete, 20 mL water was added to the reactionmixture, extracted with ethyl acetate (10 mL*3), the organic phase waswashed with 10 mL brine, dried over anhydrous sodium sulfate,concentrated, and separated by silica gel column to afford 0.31 g of alight yellow solid, yield was 70%. LC-MS(APCI): m/z=449(M+1)⁺.

Step 5. Synthesis of (R)-benzyl3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(Compound 34)

To a 50 mL sealed tube were added (R)-benzyl3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(0.31 g, 0.7 mmol) and 10 mL concentrated ammonia, the reaction washeated to 120° C. in an oil bath and reacted overnight. The reaction wascooled to room temperature after the reaction was complete, the solventwas evaporated in a rotary evaporator, to afford 0.25 g of a white solidas powder, yield was 84%. LC-MS(APCI): m/z=430(M+1)⁺.

Step 6. Synthesis of benzyl(R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(Compound 36)

(R)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(250 mg, 0.58 mmol) and (4-phenoxyphenyl)boronic acid (compound 35, 137mg, 0.64 mmol), PdCl₂(dppf)₂ (110 mg, 0.15 mmol) and potassium carbonate(160 mg, 1.16 mmol) were added to 8 mL dioxane and 2 mL water, theatmosphere was replaced by nitrogen gas for three times, the reactionwas heated to 90° C. and reacted overnight. The reaction was cooled toroom temperature after the reaction was complete, 10 mL water was added,extracted with ethyl acetate (10 mL*3), the organic phase was washedwith 10 mL brine, dried over anhydrous sodium sulfate, concentrated, andseparated by silica gel column to afford 200 mg of a light yellow solid,yield was 66%. LC-MS(APCI): m/z=520(M+1)⁺.

Step 7. Synthesis of(R)-1-(4-phenoxyphenyl)-3-(piperidin-3-yl)imidazo[1,5-a]pyrazin-8-amine(Compound 37)

(R)-benzyl

3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-carboxylate(200 mg, 0.38 mmol) and 10% Pd(OH)₂/C (40 mg) were added to 10 mLanhydrous ethanol, the atmosphere was replaced with hydrogen gas forthree times, and the mixture was stirred under 3 atmospheric pressure ofhydrogen gas at 50° C. overnight. The reaction was filtered after thereaction was complete, the filtrate was concentrated, and separated bysilica gel column to afford 125 mg of a light yellow oil, yield was 85%.LC-MS(APCI): m/z=386(M+1)⁺.

Step 8. Synthesis of(R)-1-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl)prop-2-en-1-one(Compound 38)

(R)-1-(4-phenoxyphenyl)-3-(piperidin-3-yl)imidazo[1,5-a]pyrazin-8-amine(125 mg, 0.32 mmol) and triethylamine (50 mg, 0.48 mmol) were dissolvedin 10 mL dichloromethane, cooled to −15° C., acryloyl chloride (29 mg,0.32 mmol) was slowly added dropwise, and stirred for 10 minutes afterthe addition was complete. The ice bath was removed, and the reactionwas continued for 1 hour. To the reaction mixture were added 10 mL waterand 10 mL dichloromethane, the layers were separated while stirring, theorganic phase was washed with 5 mL brine, dried over anhydrous sodiumsulfate, concentrated, and purified by column chromatography to afford100 mg of a white solid, yield was 70%. LC-MS(APCI): m/z=440(M+1)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.41 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H),7.66 (d, J=7.9 Hz, 2H), 7.50-7.38 (m, 2H), 7.26-7.07 (m, 5H), 6.79 (m,1H), 6.10 (t, J=17.7 Hz, 1H), 5.65 (dd, J=36.5, 10.9 Hz, 1H), 4.65-4.40(m, 1H), 4.25-3.65 (m, 2H), 3.08-2.91 (m, 2H), 2.25 (m, 1H), 2.11 (d,J=14.3 Hz, 1H), 1.93 (d, J=13.6 Hz, 1H), 1.60 (m, 1H).

Biological Activity Assay

(1) Kinase Inhibition Test

Reagents and Materials:

BTK (Invitrogen, catalog number: PR5442A), HTRF-TK kit (Cisbio, catalognumber: 62TK0PEC), MgCl₂ (SIGMA, catalog number: 63020-1L), ATP (Sigma,catalog number: A7699-1G), DMSO (Sigma, catalog number: D2650), BSA(Sigma, catalog number: V900933), 384-well plate (compound dilutionplate) (Greiner, catalog number: 781280), 384-well plate (test plate)(Perkin Elmer, catalog number: 6007299); XL-665 (CIS Bio International,catalog number: 610SAXL).

Experimental Procedures:

1) Compound dilution: The test compounds were dissolved in DMSO to makea 10 mM stock solution. Compounds were diluted to 1 mM in DMSO prior touse, and serially diluted (3-fold) in 384 well plates for a total of 11concentrations, with final concentrations ranging from 10 μM to 0.17 nM.2) Kinase assay: in a 10 μL reaction system (containing buffer 50 mMHepes (pH 7.5), 5 mM MgCl₂, 0.01 mM Na₃VO₄, 1% BSA) in a 384-well plate,1 nM BTK, 1 μM biotin-TK peptide (from HTRF-TK kit) and 20 μM ATP wereincubated at 23° C. for 90 minutes. 10 μL stop solution containing 20 mMEDTA, 1.67 nM TK antibody, 62.5 nM XL-665 was added and incubated at 23°C. for 60 minutes, then read with Envision.3) IC₅₀ value calculation: The inhibition rate of the compound wascalculated from the data read by the instrument, and then the IC₅₀ valuewas calculated using the mode 205 of XLFIT5 of IDBS.

Experimental Results:

The results of the kinase inhibition in the examples are summarized inTable 1 below, and the results of the experiments indicate that thecompounds disclosed herein are potent inhibitors of BTK kinase activity.

TABLE 1 Kinase inhibition Example No. BTK IC₅₀(nM) RAMOS IC₅₀(nM)Example 3 <1 <100 Example 4 <1 <100 Example 5 <1 <100 Example 6 <1 <100Example 7 <1 <100 Ibrutinib <1 <100(2) Metabolic Stability Evaluation Experiments in Microsome:

Reagents and Materials:

Human liver microsomes (0.5 mg/mL, Xenotech, catalog number: H0610); ratliver microsomes (0.5 mg/mL, Xenotech, catalog number: R1000); coenzyme(NADPH/NADH) (1 mM, Sigma Life Science); D-glucose-6-phosphate sodiumsalt (G-6-P, Aladdin, catalog number: G111871-5g); glucose-6-phosphatedehydrogenase (G-6-P D, Sigma Life Science, catalog number:G6378-250UM); magnesium chloride (5 mM), propranolol hydrochloride(Sigma, catalog number: P0884-1G); tolbutamide (Sigma Life Science,catalog number: T0891); 100 mM phosphate buffer (pH 7.4); 96-well platemixer (IKA, model: MTS 2/4 digital); 96-well deep well plate(Doublehelix Biology Science and Technology Co., Ltd, 2.2 mL); 96-wellincubator plate (Doublehelix Biology Science and Technology Co., Ltd,2.2 mL).

Experimental Procedures:

1) Preparation of stock solutions: Powder of the compounds of Examples3-7 and Ibrutinib were accurately weighed and separately dissolved inDMSO to a concentration of 5 mM.

2) Preparation of phosphate buffer (100 mM, pH 7.4): 150 mL ofpre-formulated 0.5 M potassium dihydrogen phosphate was taken and mixedwith 700 mL of 0.5 M dipotassium hydrogen phosphate solution, and the pHof the mixture was adjusted to 7.4 with 0.5 M dipotassium hydrogenphosphate solution. Before use it was diluted by 5 times with ultrapurewater, and magnesium chloride was added to obtain the phosphate buffer(100 mM), which contains 100 mM potassium phosphate, 3.3 mM magnesiumchloride, and a pH of 7.4.3) Preparation of NADPH: A reconstituted system solution (containing 6.5mM NADPH, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride) wasprepared and placed on wet ice prior to use.4) Preparation of stop solution: The stop solution was an acetonitrilesolution containing 50 ng/mL propranolol hydrochloride and 200 ng/mLtolbutamide (internal standard).5) Preparation of liver microsome dilution: 25057.5 μL phosphate buffer(pH 7.4) was taken and placed into a 50 mL centrifuge tube, 812.5 μLhuman liver microsomes was added, and evenly mixed to obtain livermicrosomes dilution with a protein concentration of 0.625 mg/mL. 25057.5μL of phosphate buffer (pH 7.4) was taken and placed into a 50 mLcentrifuge tube, 812.5 μL of SD rat liver microsomes was added, andevenly mixed to obtain a liver microsome dilution with a proteinconcentration of 0.625 mg/mL.6) Incubation of the sample: The stock solutions of the correspondingcompounds were diluted to 0.25 mM with an aqueous solution containing70% acetonitrile, which is used as a working solution and is ready foruse. 398 μL of human liver microsomes dilution or rat liver microsomedilution was added to 96-well incubation plates (N=2), and 2 μL of 0.25mM working solutions were added respectively, and evenly mixed.7) Determination of metabolic stability: 300 μL of pre-cooled stopsolution was added to each well of a 96-well deep well plate, which wasplaced on ice as a stop plate. The 96-well incubation plate and theNADPH regeneration system were placed in a 37° C. water bath, shaken at100 rpm, and pre-incubated for 5 min. 80 μL of the incubation solutionwas taken from each well of the incubation plate, added to the stopplate, evenly mixed, and 20 μL of the NADPH regeneration system solutionwas added as 0 minute sample. Then, 80 μL of the NADPH regenerationsystem solution was added to each well of the incubation plate to startthe reaction and start timing. The corresponding compound had a reactionconcentration of 1 μM and a protein concentration of 0.5 mg/mL. 100 μLof the reaction solutions were taken at 10, 30, and 90 min,respectively, added to the stop place, and the reaction was terminatedby vortexing for 3 min. The plate was centrifuged at 5000×g for 10 minat 4° C. 100 μL of the supernatant was taken and added into a 96-wellplate to which 100 μL of distilled water was previously added, evenlymixed, and samples were analyzed by LC-MS/MS.8) Data analysis: The peak area of the corresponding compounds and theinternal standard was detected by LC-MS/MS system, and the ratio of thepeak area of the compounds to the internal standard was calculated. Theslope is measured by plotting the natural logarithm of the percentage ofthe remaining amount of the compounds versus time, and t_(1/2) andCL_(int) were calculated according to the following formula, where V/Mis equal to 1/protein concentration.

${t_{1/2} = {- \frac{0.693}{slope}}},{{CL}_{int} = {\frac{{0.6}93}{t_{1/2}} \cdot \frac{V}{M}}}$

Experimental Results:

The experimental results are shown in Table 2 below. Compared withIbrutinib, the compounds disclosed herein have improved metabolicstability in human liver microsomes and rat liver microsomes, indicatingthe metabolic stability of the drug is improved.

TABLE 2 Evaluation of liver microsomes metabolism of the Examplecompounds Rat liver microsomes Human liver microsomes experimentexperiment CL_(int) CL_(int)(μL/ No. t_(1/2)(min) (μL/min/mg)t_(1/2)(min) min/mg) Ibrutinib 1.3 1096.0 1.1 1218.7  Example 3 1.31097.9 — — Example 4 3.5 399.2 2.9 483.3 Example 5 1.5 921.8 — — Example6 12.5 111.1 4.1 337.8 Example 7 5.7 242.6 2.4 576.3(3) Pharmacokinetic Experiments in Rats

8 Male Sprague-Dawley rats, 7-8 weeks old and weight of 210 g, weredivided into 2 groups, 4 rats in each group. They were intravenouslygiven 0.5 mg/kg of and orally given 10 mg/kg single dose of (a) controlgroup: reference compound; (b) test group: Example compounds. Thepharmacokinetic differences were compared.

Rats were fed with a standard diet and water. Fasting began 16 hoursbefore the test. The drug was dissolved with PEG400 and dimethylsulfoxide. Blood was collected from the eyelids at a time point of 0.083hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours,12 hours, and 24 hours after administration.

Rats were briefly anesthetized after inhalation of ether, and 300 μL ofblood samples were collected from the eyelids and placed to test tubes,wherein there were 30 μL of 1% heparin salt solution in the test tube.The tubes were dried overnight at 60° C. before use. After the bloodsample collection was completed at a later time point, the rats wereanesthetized with ether and sacrificed.

Immediately after the blood samples were collected, the test tubes weregently inverted at least 5 times to ensure sufficient mixing, and wereplaced on ice. Blood samples were centrifuged at 5000 rpm for 5 minutesat 4° C. to separate plasma from red blood cells. 100 μL of the plasmawas pipetted into a clean plastic centrifuge tube, marking the name ofthe compound and time of collection. Plasma was stored at −80° C. priorto analysis. The concentration of the compounds disclosed herein inplasma was determined by LC-MS/MS. Pharmacokinetic parameters werecalculated based on the plasma concentration of each animal at differenttime points.

The compounds disclosed herein were tested in the above pharmacokineticexperiments in rats, and the compounds disclosed herein were found tohave superior pharmacokinetic properties compared to Ibrutinib. Theresults of the pharmacokinetic experiments in rats of representativeExample 7 and the control compound Ibrutinib are summarized in Table 3below.

TABLE 3 Rat pharmacokinetic experiments of Example compounds IbrutinibExample 7 PK parameters IV PO IV PO T_(max) (h) 0.08 0.50 0.08 0.67C_(max) (ng/mL) 1228.7 250.3 965.7 364.7 AUC_(last)h*ng/mL) 437.0 727.4401.2 931.0 F(%) 16.65 23.20

It is to be understood that the examples are merely illustrative of theinvention and are not intended to limit the scope of the invention, andthe experimental methods in which the specific conditions are notindicated, are carried out generally in accordance with conventionalconditions, or in accordance with the conditions suggested by themanufacturer. Parts and percentages are parts by weight and percentageby weight unless otherwise stated.

The above is a further detailed description of the present disclosure inconnection with the specific preferred embodiments, and the specificembodiments of the present disclosure are not limited to thedescription. It will be apparent to those skilled in the art that thepresent disclosure may be practiced by making various simple deductionand replacement, without departing from the spirit and scope of theinvention.

The invention claimed is:
 1. A compound of formula (II):

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein: Ar₁ is ring C of the formula:

wherein: Y₁ is CR₂; Y₂ is CR₂; Y₃ is CR₂; Y₄ is CR₂; each R₂ isindependently H; * is the point of attachment to the nitrogen atom ofthe pyrrolo[3,2-d]pyrimidine ring or the pyrazolo[4,3-d]pyrimidine ring;and # is the point of attachment to L_(a); L_(a) is —O—; Ar₂ is phenyl;L is:

wherein: * is the point of attachment to the carbon atom of thepyrrolo[3,2-d]pyrimidine ring or the pyrazolo[4,3-d]pyrimidine ring; and# is the point of attachment to V; V is —C(O)—; R is CN, C₂-C₆ alkenyl,or C₂-C₆ alkynyl; X₃ is N; X₆ is CR₁ or N; and each R₁ is independentlyH.
 2. The compound according to claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof, wherein L is:

wherein: * is the point of attachment to the carbon atom of thepyrrolo[3,2-d]pyrimidine ring or the pyrazolo[4,3-d]pyrimidine ring; and# is the point of attachment to V.
 3. The compound according to claim 1,or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein L is:

wherein: * is the point of attachment to the carbon atom of thepyrrolo[3,2-d]pyrimidine ring or the pyrazolo[4,3-d]pyrimidine ring; and# is the point of attachment to V.
 4. The compound according to claim 1,or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein R is C₂-C₆ alkenyl.
 5. The compound according to claim1, or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein R is CH═CH₂.
 6. The compound according to claim 1,wherein the compound is of formula (IIb) or formula (IId):

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein: R is C₂-C₆ alkenyl or C₂-C₆ alkynyl.
 7. The compoundaccording to claim 1, wherein the compound is of formula (III):

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein: —L—V—R is:

wherein: * is the point of attachment to the carbon atom of thepyrrolo[3,2-d]pyrimidine ring or the pyrazolo[4,3-d]pyrimidine ring. 8.The compound according to claim 1, wherein the compound is of formula(III):

or a pharmaceutically acceptable salt or tautomer thereof, wherein:—L—V—R is:

wherein: * is the point of attachment to the carbon atom of thepyrrolo[3,2-d]pyrimidine ring or the pyrazolo[4,3-d]pyrimidine ring. 9.The compound according to claim 1, wherein the compound is:

or a pharmaceutically acceptable salt or tautomer thereof.
 10. Thecompound according to claim 1, wherein the compound is:

or a pharmaceutically acceptable salt or tautomer thereof.
 11. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and the compound according to claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof.
 12. Thepharmaceutical composition according to claim 11, wherein thepharmaceutical composition further comprises one or more additionaltherapeutic agents.